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Genome-wide microRNA Analysis Identified miR-210-3p Over-expression in Pancreatic Cancer Tissues as a Predictor of their Local Invasiveness | Anticancer Research
<!DOCTYPE html> <html lang="en" dir="ltr" xmlns="http://www.w3.org/1999/xhtml" xmlns:mml="http://www.w3.org/1998/Math/MathML"> <head prefix="og: http://ogp.me/ns# article: http://ogp.me/ns/article# book: http://ogp.me/ns/book#" > <!--[if IE]><![endif]--> <link rel="dns-prefetch" href="//cdn.jsdelivr.net" /> <link rel="dns-prefetch" href="//cdn.foxycart.com" /> <link rel="dns-prefetch" href="//scholar.google.com" /> <meta http-equiv="Content-Type" content="text/html; charset=utf-8" /> <meta name="Generator" content="Drupal 7 (http://drupal.org)" /> <link rel="canonical" href="https://ar.iiarjournals.org/content/44/11/4709" /> <link rel="alternate" type="application/pdf" title="Full Text (PDF)" href="/content/44/11/4709.full.pdf" /> <link rel="alternate" type="text/plain" title="Full Text (Plain)" href="/content/44/11/4709.full.txt" /> <link rel="alternate" type="application/vnd.ms-powerpoint" title="Powerpoint" href="/content/44/11/4709.ppt" /> <meta name="issue_cover_image" content="https://ar.iiarjournals.org/sites/default/files/highwire/anticanres/44/11.cover-source.jpg" /> <meta name="type" content="article" /> <meta name="category" content="research-article" /> <meta name="HW.identifier" content="/anticanres/44/11/4709.atom" /> <meta name="HW.pisa" content="anticanres;44/11/4709" /> <meta name="DC.Format" content="text/html" /> <meta name="DC.Language" content="en" /> <meta name="DC.Title" content="Genome-wide microRNA Analysis Identified miR-210-3p Over-expression in Pancreatic Cancer Tissues as a Predictor of their Local Invasiveness" /> <meta name="DC.Identifier" content="10.21873/anticanres.17297" /> <meta name="DC.Date" content="2024-11-01" /> <meta name="DC.Publisher" content="International Institute of Anticancer Research" /> <meta name="DC.Rights" content="Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0)." /> <meta name="DC.AccessRights" content="open-access" /> <meta name="DC.Description" content="Background/Aim: The severe malignancy of pancreatic ductal adenocarcinoma (PDAC) is mainly due to frequent local invasiveness and distant metastasis. As for local invasiveness, we previously reported that cancer-specific molecular alterations detected on resected PDAC specimen surfaces, so-called molecular surgical margin (MSM) positiveness, were significantly associated with postoperative locoregional recurrence and distant metastasis. However, due to anatomical limitations, achieving adequate surgical margins during pancreatic cancer resection is often challenging. Therefore, predicting local invasiveness based on the primary tumor’s gene profile is crucial to avoid positive MSM. Materials and Methods: Genome-wide miRNA expression profiles were examined and compared between MSM-positive and negative cases. Candidate miRNAs were evaluated in another validation cohort, and their clinicopathological characteristics were examined. Mimic or inhibitor constructs of the candidate miRNA were transfected to PDAC cell lines to evaluate the miRNA function in the pancreatic cancer cell lines and detect the downstream targets. Results: Among some candidates with highly expressed miRNAs in MSM-positive cases by miRNA expression array, recurrence-free survival (RFS) was significantly shorter in the miR-210-3p high expression group (p=0.015). High miR-210-3p was significantly associated with large tumor diameter (p=0.001), anterior invasion positive (p=0.010), and positive lymph node metastasis (p<0.001). miR-210-3p inhibition in PDAC cell lines resulted in decreased proliferation and invasiveness. The iron-sulfur cluster assembly enzyme (ISCU) gene was identified as a target of miR-210-3p. ISCU reduction was significantly observed in PDAC primary tumors with high levels of miR-210-3p, leading to mitochondrial dysfunction in miR-210-3p-overexpressing PDAC cell lines, as demonstrated by glycolysis stress tests. Conclusion: Highly expressed hypoxia-inducible miR-210-3p in primary PDAC tissues induces locally invasive characteristics through mitochondrial dysfunction by suppressing ISCU expression, which may result in poor postoperative RFS outcomes." /> <meta name="DC.Contributor" content="TOMOHISA OTSU" /> <meta name="DC.Contributor" content="MASAMICHI HAYASHI" /> <meta name="DC.Contributor" content="KEIZO FUJITA" /> <meta name="DC.Contributor" content="DAIGO KOBAYASHI" /> <meta name="DC.Contributor" content="NOBUHIKO NAKAGAWA" /> <meta name="DC.Contributor" content="KEISUKE KURIMOTO" /> <meta name="DC.Contributor" content="HIDEKI TAKAMI" /> <meta name="DC.Contributor" content="KOKI NAKANISHI" /> <meta name="DC.Contributor" content="SHINICHI UMEDA" /> <meta name="DC.Contributor" content="DAI SHIMIZU" /> <meta name="DC.Contributor" content="NORIFUMI HATTORI" /> <meta name="DC.Contributor" content="MITSURO KANDA" /> <meta name="DC.Contributor" content="CHIE TANAKA" /> <meta name="DC.Contributor" content="GORO NAKAYAMA" /> <meta name="DC.Contributor" content="YASUHIRO KODERA" /> <meta name="article:published_time" content="2024-11-01" /> <meta name="article:section" content="Experimental Studies" /> <meta name="citation_title" content="Genome-wide microRNA Analysis Identified miR-210-3p Over-expression in Pancreatic Cancer Tissues as a Predictor of their Local Invasiveness" /> <meta name="citation_abstract" lang="en" content="<p>Background/Aim: The severe malignancy of pancreatic ductal adenocarcinoma (PDAC) is mainly due to frequent local invasiveness and distant metastasis. As for local invasiveness, we previously reported that cancer-specific molecular alterations detected on resected PDAC specimen surfaces, so-called molecular surgical margin (MSM) positiveness, were significantly associated with postoperative locoregional recurrence and distant metastasis. However, due to anatomical limitations, achieving adequate surgical margins during pancreatic cancer resection is often challenging. Therefore, predicting local invasiveness based on the primary tumor’s gene profile is crucial to avoid positive MSM. Materials and Methods: Genome-wide miRNA expression profiles were examined and compared between MSM-positive and negative cases. Candidate miRNAs were evaluated in another validation cohort, and their clinicopathological characteristics were examined. Mimic or inhibitor constructs of the candidate miRNA were transfected to PDAC cell lines to evaluate the miRNA function in the pancreatic cancer cell lines and detect the downstream targets. Results: Among some candidates with highly expressed miRNAs in MSM-positive cases by miRNA expression array, recurrence-free survival (RFS) was significantly shorter in the miR-210-3p high expression group (p=0.015). High miR-210-3p was significantly associated with large tumor diameter (p=0.001), anterior invasion positive (p=0.010), and positive lymph node metastasis (p&lt;0.001). miR-210-3p inhibition in PDAC cell lines resulted in decreased proliferation and invasiveness. The iron-sulfur cluster assembly enzyme (ISCU) gene was identified as a target of miR-210-3p. ISCU reduction was significantly observed in PDAC primary tumors with high levels of miR-210-3p, leading to mitochondrial dysfunction in miR-210-3p-overexpressing PDAC cell lines, as demonstrated by glycolysis stress tests. Conclusion: Highly expressed hypoxia-inducible miR-210-3p in primary PDAC tissues induces locally invasive characteristics through mitochondrial dysfunction by suppressing ISCU expression, which may result in poor postoperative RFS outcomes.</p>" /> <meta name="citation_journal_title" content="Anticancer Research" /> <meta name="citation_publisher" content="International Institute of Anticancer Research" /> <meta name="citation_publication_date" content="2024/11/01" /> <meta name="citation_mjid" content="anticanres;44/11/4709" /> <meta name="citation_id" content="44/11/4709" /> <meta name="citation_public_url" content="https://ar.iiarjournals.org/content/44/11/4709" /> <meta name="citation_abstract_html_url" content="https://ar.iiarjournals.org/content/44/11/4709.abstract" /> <meta name="citation_full_html_url" content="https://ar.iiarjournals.org/content/44/11/4709.full" /> <meta name="citation_pdf_url" content="https://ar.iiarjournals.org/content/anticanres/44/11/4709.full.pdf" /> <meta name="citation_issn" content="0250-7005" /> <meta name="citation_issn" content="1791-7530" /> <meta name="citation_doi" content="10.21873/anticanres.17297" /> <meta name="citation_pmid" content="39477289" /> <meta name="citation_volume" content="44" /> <meta name="citation_issue" content="11" /> <meta name="citation_article_type" content="Research Article" /> <meta name="citation_section" content="Experimental Studies" /> <meta name="citation_firstpage" content="4709" /> <meta name="citation_lastpage" content="4721" /> <meta name="citation_access" content="all" /> <meta name="citation_author" content="TOMOHISA OTSU" /> <meta name="citation_author_institution" content="Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan" /> <meta name="citation_author" content="MASAMICHI HAYASHI" /> <meta name="citation_author_institution" content="Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan" /> <meta name="citation_author_email" content="hayashi.masamichi.b9@f.mail.nagoya-u.ac.jp" /> <meta name="citation_author" content="KEIZO FUJITA" /> <meta name="citation_author_institution" content="Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan" /> <meta name="citation_author" content="DAIGO KOBAYASHI" /> <meta name="citation_author_institution" content="Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan" /> <meta name="citation_author" content="NOBUHIKO NAKAGAWA" /> <meta name="citation_author_institution" content="Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan" /> <meta name="citation_author" content="KEISUKE KURIMOTO" /> <meta name="citation_author_institution" content="Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan" /> <meta name="citation_author" content="HIDEKI TAKAMI" /> <meta name="citation_author_institution" content="Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan" /> <meta name="citation_author" content="KOKI NAKANISHI" /> <meta name="citation_author_institution" content="Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan" /> <meta name="citation_author" content="SHINICHI UMEDA" /> <meta name="citation_author_institution" content="Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan" /> <meta name="citation_author" content="DAI SHIMIZU" /> <meta name="citation_author_institution" content="Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan" /> <meta name="citation_author" content="NORIFUMI HATTORI" /> <meta name="citation_author_institution" content="Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan" /> <meta name="citation_author" content="MITSURO KANDA" /> <meta name="citation_author_institution" content="Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan" /> <meta name="citation_author" content="CHIE TANAKA" /> <meta name="citation_author_institution" content="Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan" /> <meta name="citation_author" content="GORO NAKAYAMA" /> <meta name="citation_author_institution" content="Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan" /> <meta name="citation_author" content="YASUHIRO KODERA" /> <meta name="citation_author_institution" content="Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan" /> <meta name="citation_reference" content="citation_journal_title=CA Cancer J Clin;citation_author=RL. 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Kodera;citation_title=Impact of molecular surgical margin analysis on the prediction of pancreatic cancer recurrences after pancreaticoduodenectomy;citation_pages=172;citation_volume=13;citation_year=2021;citation_issue=1;citation_pmid=34530906;citation_doi=10.1186/s13148-021-01165-8" /> <meta name="citation_fulltext_world_readable" content="" /> <meta name="twitter:title" content="Genome-wide microRNA Analysis Identified miR-210-3p Over-expression in Pancreatic Cancer Tissues as a Predictor of their Local Invasiveness" /> <meta name="twitter:card" content="summary_large_image" /> <meta name="twitter:image" content="https://ar.iiarjournals.org/sites/default/files/highwire/anticanres/44/11.cover-source.jpg" /> <meta name="twitter:description" content="Background/Aim: The severe malignancy of pancreatic ductal adenocarcinoma (PDAC) is mainly due to frequent local invasiveness and distant metastasis. As for local invasiveness, we previously reported that cancer-specific molecular alterations detected on resected PDAC specimen surfaces, so-called molecular surgical margin (MSM) positiveness, were significantly associated with postoperative locoregional recurrence and distant metastasis. However, due to anatomical limitations, achieving adequate surgical margins during pancreatic cancer resection is often challenging. Therefore, predicting local invasiveness based on the primary tumor’s gene profile is crucial to avoid positive MSM. Materials and Methods: Genome-wide miRNA expression profiles were examined and compared between MSM-positive and negative cases. Candidate miRNAs were evaluated in another validation cohort, and their clinicopathological characteristics were examined. Mimic or inhibitor constructs of the candidate miRNA were transfected to PDAC cell lines to evaluate the miRNA function in the pancreatic cancer cell lines and detect the downstream targets. Results: Among some candidates with highly expressed miRNAs in MSM-positive cases by miRNA expression array, recurrence-free survival (RFS) was significantly shorter in the miR-210-3p high expression group (p=0.015). High miR-210-3p was significantly associated with large tumor diameter (p=0.001), anterior invasion positive (p=0.010), and positive lymph node metastasis (p<0.001). miR-210-3p inhibition in PDAC cell lines resulted in decreased proliferation and invasiveness. The iron-sulfur cluster assembly enzyme (ISCU) gene was identified as a target of miR-210-3p. ISCU reduction was significantly observed in PDAC primary tumors with high levels of miR-210-3p, leading to mitochondrial dysfunction in miR-210-3p-overexpressing PDAC cell lines, as demonstrated by glycolysis stress tests. Conclusion: Highly expressed hypoxia-inducible miR-210-3p in primary PDAC tissues induces locally invasive characteristics through mitochondrial dysfunction by suppressing ISCU expression, which may result in poor postoperative RFS outcomes." /> <meta name="og-title" property="og:title" content="Genome-wide microRNA Analysis Identified miR-210-3p Over-expression in Pancreatic Cancer Tissues as a Predictor of their Local Invasiveness" /> <meta name="og-url" property="og:url" content="https://ar.iiarjournals.org/content/44/11/4709" /> <meta name="og-site-name" property="og:site_name" content="Anticancer Research" /> <meta name="og-description" property="og:description" content="Background/Aim: The severe malignancy of pancreatic ductal adenocarcinoma (PDAC) is mainly due to frequent local invasiveness and distant metastasis. As for local invasiveness, we previously reported that cancer-specific molecular alterations detected on resected PDAC specimen surfaces, so-called molecular surgical margin (MSM) positiveness, were significantly associated with postoperative locoregional recurrence and distant metastasis. However, due to anatomical limitations, achieving adequate surgical margins during pancreatic cancer resection is often challenging. Therefore, predicting local invasiveness based on the primary tumor’s gene profile is crucial to avoid positive MSM. Materials and Methods: Genome-wide miRNA expression profiles were examined and compared between MSM-positive and negative cases. Candidate miRNAs were evaluated in another validation cohort, and their clinicopathological characteristics were examined. Mimic or inhibitor constructs of the candidate miRNA were transfected to PDAC cell lines to evaluate the miRNA function in the pancreatic cancer cell lines and detect the downstream targets. Results: Among some candidates with highly expressed miRNAs in MSM-positive cases by miRNA expression array, recurrence-free survival (RFS) was significantly shorter in the miR-210-3p high expression group (p=0.015). High miR-210-3p was significantly associated with large tumor diameter (p=0.001), anterior invasion positive (p=0.010), and positive lymph node metastasis (p<0.001). miR-210-3p inhibition in PDAC cell lines resulted in decreased proliferation and invasiveness. The iron-sulfur cluster assembly enzyme (ISCU) gene was identified as a target of miR-210-3p. ISCU reduction was significantly observed in PDAC primary tumors with high levels of miR-210-3p, leading to mitochondrial dysfunction in miR-210-3p-overexpressing PDAC cell lines, as demonstrated by glycolysis stress tests. Conclusion: Highly expressed hypoxia-inducible miR-210-3p in primary PDAC tissues induces locally invasive characteristics through mitochondrial dysfunction by suppressing ISCU expression, which may result in poor postoperative RFS outcomes." /> <meta name="og-type" property="og:type" content="article" /> <meta name="og-image" property="og:image" content="https://ar.iiarjournals.org/sites/default/files/highwire/anticanres/44/11.cover-source.jpg" /> <link rel="shortlink" href="/node/82128" /> <link rel="shortcut icon" href="https://ar.iiarjournals.org/sites/default/files/images/favicon.ico" type="image/vnd.microsoft.icon" /> <meta name="viewport" content="width=device-width, initial-scale=1" /> <title>Genome-wide microRNA Analysis Identified miR-210-3p Over-expression in Pancreatic Cancer Tissues as a Predictor of their Local Invasiveness | Anticancer Research</title> <link type="text/css" rel="stylesheet" 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class="highwire-cite highwire-cite-highwire-article highwire-citation-jcore-article-title-complete clearfix has-author-tooltip highwire-citation-highwire-article-top-a"> <div class="highwire-cite-overline"><span class="highwire-cite-metadata-article-type highwire-cite-metadata">Research Article</span><span class="separator-pipe"></span><span class="highwire-cite-metadata-art-cat highwire-cite-metadata"><span class="wrapper">Experimental Studies</span></span></div> <div class="highwire-cite-access"><span class="highwire-citation-access"><i class="highwire-access-icon highwire-access-icon-open-access open-access hw-icon-open-access" title="Open Access" aria-hidden="true"></i><span class="element-invisible highwire-access-icon highwire-access-icon-open-access" style="">Open Access</span></span></div> <h1 class="highwire-cite-title" id="page-title">Genome-wide microRNA Analysis Identified <em>miR-210-3p</em> Over-expression in Pancreatic Cancer Tissues as a Predictor of their Local Invasiveness</h1> <div class="highwire-cite-authors"><span class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0">TOMOHISA OTSU</span>, <span class="highwire-citation-author" data-delta="1">MASAMICHI HAYASHI</span>, <span class="highwire-citation-author" data-delta="2">KEIZO FUJITA</span>, <span class="highwire-citation-author" data-delta="3">DAIGO KOBAYASHI</span>, <span class="highwire-citation-author" data-delta="4">NOBUHIKO NAKAGAWA</span>, <span class="highwire-citation-author" data-delta="5">KEISUKE KURIMOTO</span>, <span class="highwire-citation-author" data-delta="6">HIDEKI TAKAMI</span>, <span class="highwire-citation-author" data-delta="7">KOKI NAKANISHI</span>, <span class="highwire-citation-author" data-delta="8">SHINICHI UMEDA</span>, <span class="highwire-citation-author" data-delta="9">DAI SHIMIZU</span>, <span class="highwire-citation-author" data-delta="10">NORIFUMI HATTORI</span>, <span class="highwire-citation-author" data-delta="11">MITSURO KANDA</span>, <span class="highwire-citation-author" data-delta="12">CHIE TANAKA</span>, <span class="highwire-citation-author" data-delta="13">GORO NAKAYAMA</span> and <span class="highwire-citation-author" data-delta="14">YASUHIRO KODERA</span></span></div> <div class="highwire-cite-metadata"><span class="highwire-cite-metadata-journal highwire-cite-metadata">Anticancer Research </span><span class="highwire-cite-metadata-date highwire-cite-metadata">November 2024, </span><span class="highwire-cite-metadata-volume highwire-cite-metadata">44 </span><span class="highwire-cite-metadata-issue highwire-cite-metadata">(11) </span><span class="highwire-cite-metadata-pages highwire-cite-metadata">4709-4721; </span><span class="highwire-cite-metadata-doi highwire-cite-metadata">DOI: https://doi.org/10.21873/anticanres.17297 </span></div> <div class="highwire-cite-extras"><span class="highwire-foxycart-add-to-cart-ahah highwire-foxycart-add-to-cart-ahah" data-text="Add to Cart (%short-price)" data-apath="/anticanres/44/11/4709.atom" data-type="link" data-font-icon="" data-parent-id="81985"></span></div> </div> <div id="hw-article-author-popups-top-node-82128--6184144554" style="display: none;"><div class="author-tooltip-0"><div class="author-tooltip-name">TOMOHISA OTSU </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'>Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=TOMOHISA%2BOTSU%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=OTSU%20T&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3ATOMOHISA%2BOTSU%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-1"><div class="author-tooltip-name">MASAMICHI HAYASHI </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'>Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=MASAMICHI%2BHAYASHI%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=HAYASHI%20M&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AMASAMICHI%2BHAYASHI%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-corresp-email-link last"><span>For correspondence: <a href="mailto:hayashi.masamichi.b9@f.mail.nagoya-u.ac.jp" class="" data-icon-position="" data-hide-link-title="0">hayashi.masamichi.b9@f.mail.nagoya-u.ac.jp</a></span></li></ul></div><div class="author-tooltip-2"><div class="author-tooltip-name">KEIZO FUJITA </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'>Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=KEIZO%2BFUJITA%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=FUJITA%20K&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AKEIZO%2BFUJITA%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-3"><div class="author-tooltip-name">DAIGO KOBAYASHI </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'>Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, 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class="panel-panel panel-col"> <div><div class="panel-pane pane-highwire-markup" > <div class="pane-content"> <div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" data-highwire-cite-ref-tooltip-instance="highwire_reflinks_tooltip" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="article fulltext-view "><span class="highwire-journal-article-marker-start"></span><div class="section abstract" id="abstract-1"><h2>Abstract</h2><p id="p-4">Background/Aim: The severe malignancy of pancreatic ductal adenocarcinoma (PDAC) is mainly due to frequent local invasiveness and distant metastasis. As for local invasiveness, we previously reported that cancer-specific molecular alterations detected on resected PDAC specimen surfaces, so-called molecular surgical margin (MSM) positiveness, were significantly associated with postoperative locoregional recurrence and distant metastasis. However, due to anatomical limitations, achieving adequate surgical margins during pancreatic cancer resection is often challenging. Therefore, predicting local invasiveness based on the primary tumor’s gene profile is crucial to avoid positive MSM. Materials and Methods: Genome-wide miRNA expression profiles were examined and compared between MSM-positive and negative cases. Candidate miRNAs were evaluated in another validation cohort, and their clinicopathological characteristics were examined. Mimic or inhibitor constructs of the candidate miRNA were transfected to PDAC cell lines to evaluate the miRNA function in the pancreatic cancer cell lines and detect the downstream targets. Results: Among some candidates with highly expressed miRNAs in MSM-positive cases by miRNA expression array, recurrence-free survival (RFS) was significantly shorter in the miR-210-3p high expression group (p=0.015). High miR-210-3p was significantly associated with large tumor diameter (p=0.001), anterior invasion positive (p=0.010), and positive lymph node metastasis (p<0.001). miR-210-3p inhibition in PDAC cell lines resulted in decreased proliferation and invasiveness. The iron-sulfur cluster assembly enzyme (ISCU) gene was identified as a target of miR-210-3p. ISCU reduction was significantly observed in PDAC primary tumors with high levels of miR-210-3p, leading to mitochondrial dysfunction in miR-210-3p-overexpressing PDAC cell lines, as demonstrated by glycolysis stress tests. Conclusion: Highly expressed hypoxia-inducible miR-210-3p in primary PDAC tissues induces locally invasive characteristics through mitochondrial dysfunction by suppressing ISCU expression, which may result in poor postoperative RFS outcomes.</p></div><span class="kwd-group-title">Key Words:</span><ul class="kwd-group"><li class="kwd"><a href="/keyword/pancreatic-cancer" class="hw-term hw-article-keyword hw-article-keyword-pancreatic-cancer" rel="nofollow">Pancreatic cancer</a></li><li class="kwd"><a xmlns:default="http://www.w3.org/1999/xhtml" href="/keyword/mir-210-3p" class="hw-term hw-article-keyword hw-article-keyword-mir-210-3p" rel="nofollow"><em xmlns:default="http://www.w3.org/1999/xhtml">miR-210-3p</em></a></li><li class="kwd"><a href="/keyword/iscu" class="hw-term hw-article-keyword hw-article-keyword-iscu" rel="nofollow">ISCU</a></li><li class="kwd"><a href="/keyword/recurrence-free-survival" class="hw-term hw-article-keyword hw-article-keyword-recurrence-free-survival" rel="nofollow">recurrence-free survival</a></li><li class="kwd"><a href="/keyword/local-invasiveness" class="hw-term hw-article-keyword hw-article-keyword-local-invasiveness" rel="nofollow">local invasiveness</a></li></ul><p id="p-5">Despite significant advancements in diagnostic technology and multidisciplinary treatment, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains poor, and the 5-year survival rate after diagnosis is approximately 10% for all stages (<a id="xref-ref-1-1" class="xref-bibr" href="#ref-1">1</a>). One of the critical causes of frequent postoperative recurrence of PDAC is the tendency for intensive local invasion, and histologically positive surgical margin status severely influences the frequency of postoperative recurrences (<a id="xref-ref-2-1" class="xref-bibr" href="#ref-2">2</a>). Moreover, some histologically margin-negative cases still show cancer relapse after surgery. One reason is the difficulty in histologically diagnosing surgical margin specimens that are uneven, affected by preoperative therapy, or exhibit invisible field cancerizations (<a id="xref-ref-3-1" class="xref-bibr" href="#ref-3">3</a>). To evaluate surgical margin status more precisely, we previously applied and reported molecular surgical margin (MSM) analysis for resected PDAC cases with histologically negative surgical margins (<a id="xref-ref-4-1" class="xref-bibr" href="#ref-4">4</a>).</p><p id="p-6">While surgeries for pancreatic cancer are performed with a focus on the primary tumor location and visible tumor spread by CT images, it is sometimes impossible to maintain sufficient surgical margins around the pancreas because of anatomical limitations. If the preoperatively estimated surgical margin is positive, additional chemoradiotherapy would be a choice to manage the cancer. In this situation, markers from the primary tumor’s gene profile that predict positive MSM are essential for determining the treatment strategy.</p><p id="p-7">This study focused on the alterations of microRNAs (miRNAs) in the primary tumor, which are single-stranded noncoding RNAs consisting of 18-25 nucleotides that regulate target mRNA stability and translational efficiency. Dysregulation of miRNAs in cancer cells usually disrupts cellular homeostasis and leads to misregulated senescence. It exerts abnormal functions in the oncogenesis and metastasis process of numerous tumors (<a id="xref-ref-5-1" class="xref-bibr" href="#ref-5">5</a>, <a id="xref-ref-6-1" class="xref-bibr" href="#ref-6">6</a>). Various studies have also identified miRNAs associated with human PDAC carcinogenesis (<a id="xref-ref-7-1" class="xref-bibr" href="#ref-7">7</a>-<a id="xref-ref-9-1" class="xref-bibr" href="#ref-9">9</a>). However, miRNAs associated with primary tumor invasiveness in PDAC are unknown. We compared genome-wide miRNA expression results of four primary PDAC tissues from MSM-positive and four from MSM-negative cases. We also used 110 PDAC samples as a validation cohort to confirm candidate miRNAs. We further explored the potential pathways of the candidate miRNAs identified in this study using <em>in vitro</em> assays.</p><div class="section materials-methods" id="sec-1"><h2 class="">Materials and Methods</h2><p id="p-8"><em>Sample collection</em>. RNA samples were extracted from a test cohort of four primary PDAC tissues from MSM-positive cases and four from MSM-negative cases. All cases underwent subtotal stomach-preserving pancreaticoduodenectomy (SSPPD). All cases had histologically negative surgical margins. However, MSM-positive cases had invisible cancer-specific gene alteration-containing cells on the cutting margin surface, and cancer relapses occurred in all four MSM-positive cases. No recurrence was found in the four MSM-negative cases (<a id="xref-table-wrap-1-1" class="xref-table" href="#T1">Table I</a>).</p><div id="T1" class="table pos-float"><div class="table-inline table-callout-links"><div class="callout"><span>View this table:</span><ul class="callout-links"><li class="view-inline first"><a href="" class="table-expand-inline" data-table-url="/highwire/markup/82314/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed&table-expand-inline=1" data-icon-position="" data-hide-link-title="0">View inline</a></li><li class="view-popup"><a href="/highwire/markup/82314/expansion?width=1000&height=500&iframe=true&postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed" class="colorbox colorbox-load table-expand-popup" rel="gallery-fragment-tables" data-icon-position="" data-hide-link-title="0">View popup</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/82314" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div></div><div class="table-caption"><span class="table-label">Table I.</span> <p id="p-9" class="first-child">Training cohort.</p><div class="sb-div caption-clear"></div></div></div><p id="p-10">Another RNA sample cohort of 110 PDAC-resected cases between November 2016 and February 2020 was prepared as a validation cohort. Histological staging was defined using the TNM staging system by the Union for International Cancer Control (UICC) 8th edition. The Review Board of Nagoya University approved the sample collection protocol (2014-0042), and written informed consent for surgical sample use was obtained from all patients included in this study.</p><p id="p-11"><em>Human miRNA microarray</em>. RNA samples from PDAC primary tumors of four MSM-positive and four MSM-negative cases were outsourced to perform genome-wide miRNA microarray [SurePrint G3 Human miRNA microarray 8x60K (Agilent Technologies, Santa Clara, CA, USA)].</p><p id="p-12"><em>Publicly available dataset and bioinformatics analysis</em>. Normalized RNA sequencing data for pancreatic adenocarcinoma (PAAD) from The Cancer Genome Atlas (TCGA) were downloaded from the UCSC Xena server. This dataset included 223 pancreatic cancer cases with overall survival (OS) data. The bioinformatics tool miRDB was used to predict downstream targets of <em>miR-210-3p</em> in PDAC.</p><p id="p-13"><em>qRT-PCR of miRNA expression</em>. Following the manufacturer’s protocol, the total RNA was isolated from frozen surgical samples or cell lines using an RNeasy Mini Kit (Qiagen, Hilden, Germany). Only sections with more than 70% tumor cells were used for RNA extraction. The quantity and quality of the total RNA were verified with a NanoDrop spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA). Next, 10 ng of RNA was reverse transcribed using a TaqMan reverse transcription kit (Applied Biosystems, Foster City, CA, USA). qRT-PCR was performed using miRNA-specific primers provided with TaqMan miRNA assays (Applied Biosystems) in a 15 μl reaction volume containing 3 μl of RT primer mix, 0.15 μl of 100-mmol/l deoxyribonucleotides (NTPs), 1 μl of reverse transcriptase (50 U/μl), 1.5 μl of ×10 reverse transcription buffer, 0.19 μl of RNase inhibitor (20 U/μl), 4.16 μl of nuclease-free water, and 5 μl of RNA (10 ng). Reactions were performed by annealing at 16°C for 30 min, followed by extension at 42°C for 30 min. Next, 1.3 μl of the reaction was combined with 1 μl of specific primers for each miRNA (Applied Biosystems) and analyzed using an ABI Step One Plus Real-Time PCR System (Applied Biosystems). The thermal cycling parameters were 50°C for 2 min and 95°C for 10 min, followed by denaturation at 95°C for 15 s and annealing/extension at 60°C for 1 min for 45 cycles. All experiments were performed in triplicate. Step One Plus software v2.3 (Applied Biosystems) was used to obtain raw threshold cycle (Ct) values. Relative miRNA expression was calculated with the 2<sup>−ΔΔCt</sup> method using <em>RNU6B</em> as an internal control.</p><p id="p-14"><em>qRT-PCR of mRNA expression</em>. Complementary DNA (cDNA) was synthesized with the q Script cDNA SuperMix (Quanta Biosciences, Beverly, MA, USA) with 1 μg of total RNA. Reactions were performed using SYBR Premix Ex Taq II (Takara Bio Inc., Shiga, Japan) with the following conditions: 1 cycle of 95°C for 10 s, followed by 40 cycles of 95°C for 5 s, and 60°C for 30 s. Reactions were run in triplicate. Real-time detection of emission intensity was conducted with StepOnePlus (Thermo Fisher Scientific). The qPCR forward primer and reverse primer sequences for iron-sulfur cluster assembly enzyme (<em>ISCU</em>) were 5′-GGCCCGACTCTATCACAAGA-3′ and 5′-CACCAGTCCAGTTCCAACAT-3′, respectively (<a id="xref-ref-10-1" class="xref-bibr" href="#ref-10">10</a>). Actin type B (<em>ACTB</em>) (forward: 5′-CACCATTGGCAATGAGCGGTTC-3′, reverse: 5′-AGGTCTTTGCGGATGTCCACGT-3′) was used as an internal control. Gene expression levels were calculated by using the 2<sup>−ΔΔCt</sup> method.</p><p id="p-15"><em>Cell lines and cell culture</em>. Thirteen PDAC cell lines (HPAF-II, Capan-1, KP1NL, Capan-2, MPanc96, PATU8902, COLO357, AsPC-1, BxPC3, Panc-1, MiaPaca-2, PATU8988, SW1990) were obtained from the American Type Culture Collection (Manassas, VA, USA) and cultured following the cell culture recommendations for each cell line. Cell lines were cultured in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with penicillin, streptomycin, and 10% fetal bovine serum (Thermo Fisher Scientific) at 37°C in a 5% CO<sub>2</sub> incubator.</p><p id="p-16"><em>Cell transfection</em>. Cells (2×10<sup>5</sup> cells/well in 2.5 ml DMEM) seeded into 6-well plates were transfected with mirVana™ inhibitor construct for SW1990 and MiaPaca-2, and mirVana™ mimic construct for Capan-1 and PATU8902 at 50 nM using Lipofectamine RNAiMAX (Thermo Fisher Scientific) following the manufacturer’s protocol. mirVana miRNA inhibitor Negative Control #1 and mirVana miRNA mimic Negative Control #1 (Thermo Fisher Scientific) were used as controls. Transfected cells were collected at 48 h after transfection and applied to downstream assays.</p><p id="p-17"><em>Cell proliferation assay</em>. Transfected cells were seeded into a 96-well plate. Cell proliferation was measured at different time points (24, 48, and 72 h after seeding) using a Cell Counting Kit-8 (Dojindo, Kumamoto, Japan) following the manufacturer’s instructions. Briefly, 10 μl of reagent was added to each well. After incubation in the dark for 2 h at 37°C, the absorbance was measured by spectrophotometric readings (450 nm). All assays were performed in triplicate, and each experiment was repeated at least twice. Cell proliferation values were calculated as a percentage of the value at each time point relative to the value at baseline.</p><p id="p-18"><em>Cell invasion assay</em>. Invasion assays were performed using the Corning BioCoat™ invasion chamber with Matrigel™ matrix and uncoated control inserts following the manufacturer’s instructions. Cells on the surface of the membrane were fixed and stained with Diff-Quik (Sysmex, Kobe, Japan) and washed with distilled water. Cell nuclei was stained in purple, and the cytoplasm was stained in pink. Afterward, the membrane was cut to make slides, and membrane-passing cells were counted microscopically. Cell invasion status was judged by the ratio of Matrigel™ matrix coated membrane-passing cells to uncoated membrane-passing cells.</p><p id="p-19"><em>Glycolysis stress test</em>. We used the Seahorse XF glycolysis stress kit of Seahorse XFp, an extracellular flux analyzer system (Agilent Technologies, Santa Clara, CA, USA), following the manufacturer’s protocol. Cells were inoculated into the cartridge (2×10<sup>4</sup> cells per well) the day before measurement. After counting the cells, the medium was changed to a pH-adjusted XF Base Medium with glutamine solution. Glucose, oligomycin, and 2-deoxy-D-glucose were applied to each injection port of the cartridge, and the sample was loaded to the analyzer. The results were analyzed using Wave software (Agilent Technologies, Santa Clara, CA, USA).</p><p id="p-20"><em>Western blotting</em>. Cultured cells were washed and lysed by using Pierce RIPA buffer (Thermo Fisher Scientific). The protein lysates were homogenized, and the supernatant was collected after centrifugation. Protein concentration was calculated using the Pierce BCA Protein Assay Kit (Takara Bio, Ohtsu, Japan). Equal concentrations of protein samples were loaded onto a 12-230 kDa Wes Separation Module (Protein Simple, San Jose, CA, USA) and analyzed with rabbit anti-ISCU primary antibody (ab154060, Abcam, Cambridge, UK) following the manufacturer’s protocol for the Wes system (Protein Simple). A mouse monoclonal anti-beta-actin antibody (#3700; Cell Signaling Technology, Danvers, MA, USA) was used for internal control.</p><p id="p-21"><em>Statistical analysis</em>. Clinicopathological variables were analyzed using Fisher’s exact test. Recurrence-free survival (RFS) was defined as the time from surgery to the first documentation of disease recurrence. Associations of histopathological factors with RFS were evaluated by using the log-rank test or Cox proportional hazards model with hazard ratios (HRs) and 95% confidence intervals (95%CIs). <em>p</em>-Value <0.05 was considered statistically significant. Statistical analyses were performed using the JMP Pro software program, version 16 (SAS Institute, Cary, NC, USA).</p></div><div class="section results" id="sec-2"><h2 class="">Results</h2><p id="p-22"><em>Differentially expressed miRNAs between primary PDAC tissues of MSM-positive and MSM-negative cases</em>. We performed miRNA array analysis on PDAC tumor tissues from patients with MSM-positive and MSM-negative status. We identified several miRNAs showing significantly different expression levels between the two groups (over |4-fold or under 0.25-fold) (<a id="xref-table-wrap-2-1" class="xref-table" href="#T2">Table II</a>). In MSM-positive cases, <em>miR-210-3p, let-7d-3p, miR-32-3p, miR-198</em>, and <em>miR-378b</em> were elevated more than fourfold compared to MSM-negative cases. While <em>miR-451a, miR-146a-5p, miR-150-5p, miR-126-3p, miR-20a-5p, miR-17-5p, miR-29b-3p, miR-15a-5p</em>, and <em>miR-195-5p</em> were decreased to less than one-fourth of the levels found in MSM-negative cases. Among these candidates, we examined their impacts on patient survival outcomes using the TCGA pancreatic cancer database, as invasive characteristics may influence these outcomes. Markedly different survival outcomes were observed between high and low expression cases for three miRNAs: <em>miR-210-3p</em> (<em>p</em>=0.062), <em>miR-126-3p</em> (<em>p</em>=0.023), and <em>miR-15a-5p</em> (<em>p</em><0.001) (<a id="xref-table-wrap-2-2" class="xref-table" href="#T2">Table II</a>).</p><div id="T2" class="table pos-float"><div class="table-inline table-callout-links"><div class="callout"><span>View this table:</span><ul class="callout-links"><li class="view-inline first"><a href="" class="table-expand-inline" data-table-url="/highwire/markup/82072/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed&table-expand-inline=1" data-icon-position="" data-hide-link-title="0">View inline</a></li><li class="view-popup"><a href="/highwire/markup/82072/expansion?width=1000&height=500&iframe=true&postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed" class="colorbox colorbox-load table-expand-popup" rel="gallery-fragment-tables" data-icon-position="" data-hide-link-title="0">View popup</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/82072" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div></div><div class="table-caption"><span class="table-label">Table II.</span> <p id="p-23" class="first-child">Candidate miRNA expression specific for molecular surgical margin (MSM)-positive pancreatic ductal adenocarcinoma (>4 or <0.25-fold).</p><div class="sb-div caption-clear"></div></div></div><p id="p-24"><em>Survival outcomes depending on candidate miRNA expression levels in the validation cohort</em>. We used a cohort of 110 PDAC resected cases to validate the above results. The characteristics of the patient cohort are shown in <a id="xref-table-wrap-3-1" class="xref-table" href="#T3">Table III</a>. We analyzed the candidate miRNA expression levels in the cohort, and the Kaplan–Meier curve was performed using the median values as cut-offs. RFS was significantly shorter in the <em>miR-210-3p</em> high-expression group than in the low-expression group (<em>p</em>=0.015); the median RFS time was 15.1 months in the high-expression group and 24.3 months in the low-expression group. No significant difference in RFS was observed for <em>miR-126-3p</em> and <em>miR-15a-5p</em> expression (<a id="xref-fig-1-1" class="xref-fig" href="#F1">Figure 1</a>). Therefore, we selected <em>miR-210-3p</em> for subsequent analysis as a candidate cancer invasiveness–related miRNA.</p><div id="T3" class="table pos-float"><div class="table-inline table-callout-links"><div class="callout"><span>View this table:</span><ul class="callout-links"><li class="view-inline first"><a href="" class="table-expand-inline" data-table-url="/highwire/markup/82264/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed&table-expand-inline=1" data-icon-position="" data-hide-link-title="0">View inline</a></li><li class="view-popup"><a href="/highwire/markup/82264/expansion?width=1000&height=500&iframe=true&postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed" class="colorbox colorbox-load table-expand-popup" rel="gallery-fragment-tables" data-icon-position="" data-hide-link-title="0">View popup</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/82264" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div></div><div class="table-caption"><span class="table-label">Table III.</span> <p id="p-25" class="first-child">Patient characteristics of validation cohort.</p><div class="sb-div caption-clear"></div></div></div><div id="F1" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F1.large.jpg?width=800&height=600&carousel=1" title="Kaplan–Meier analysis of recurrence-free survival (RFS). Patients with primary pancreatic ductal adenocarcinoma with high miR-210-3p expression showed significantly worse postoperative RFS (p=0.015); RFS was not significantly different between miR-126-3p and miR-15a-5p high and low expression groups. MST: Median survival time." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-1269938803" data-figure-caption="<div class="highwire-markup">Kaplan–Meier analysis of recurrence-free survival (RFS). Patients with primary pancreatic ductal adenocarcinoma with high miR-210-3p expression showed significantly worse postoperative RFS (p=0.015); RFS was not significantly different between miR-126-3p and miR-15a-5p high and low expression groups. MST: Median survival time.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 1." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F1.medium.gif" width="410" height="440"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 1." src="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F1.medium.gif" width="410" height="440"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F1.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 1." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F1.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/82260" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption" xmlns:xhtml="http://www.w3.org/1999/xhtml"><span class="fig-label">Figure 1.</span> <p id="p-26" class="first-child">Kaplan–Meier analysis of recurrence-free survival (RFS). Patients with primary pancreatic ductal adenocarcinoma with high miR-210-3p expression showed significantly worse postoperative RFS (p=0.015); RFS was not significantly different between miR-126-3p and miR-15a-5p high and low expression groups. MST: Median survival time.</p><div class="sb-div caption-clear"></div></div></div><p id="p-27"><em>Clinical features of high miR-210-3p expression cases in the validation cohort</em>. The clinic-histological differences between <em>miR-210-3p</em> high and low expression cases in the validation cohort are shown in <a id="xref-table-wrap-4-1" class="xref-table" href="#T4">Table IV</a>. High <em>miR-210-3p</em> expression PDAC cases tended to be resectable (<em>p</em><0.001), with no neoadjuvant therapy (<em>p</em>=0.001), a large tumor diameter (>20 mm) (<em>p</em>=0.001), positive serosal invasion (<em>p</em>=0.010) and positive lymph node metastasis (<em>p</em><0.001).</p><div id="T4" class="table pos-float"><div class="table-inline table-callout-links"><div class="callout"><span>View this table:</span><ul class="callout-links"><li class="view-inline first"><a href="" class="table-expand-inline" data-table-url="/highwire/markup/82310/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed&table-expand-inline=1" data-icon-position="" data-hide-link-title="0">View inline</a></li><li class="view-popup"><a href="/highwire/markup/82310/expansion?width=1000&height=500&iframe=true&postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed" class="colorbox colorbox-load table-expand-popup" rel="gallery-fragment-tables" data-icon-position="" data-hide-link-title="0">View popup</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/82310" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div></div><div class="table-caption"><span class="table-label">Table IV.</span> <p id="p-28" class="first-child">miR-210-3p and clinicopathological characteristics.</p><div class="sb-div caption-clear"></div></div></div><p id="p-29">The Cox proportional hazards model was applied to analyze the RFS outcomes in the cohort. Univariate analysis showed that poor prognosis was significantly associated with elevated CA19-9 levels (HR=2.02; 95%CI=1.10-3.71; <em>p</em>=0.024), tumor diameter >20 mm (HR=2.04; 95%CI=1.18-3.53; <em>p</em>=0.010), positive serosal invasion (HR=3.62; 95%CI=1.64-7.98; <em>p</em>=0.001), positive retroperitoneal invasion (HR=3.49; 95%CI= 1.40-8.71; <em>p</em>=0.007), positive lymphatic invasion (HR=2.23; 95%CI=1.31-3.82; <em>p</em>=0.003), positive venous invasion (HR=1.73; 95%CI=1.07-2.80; <em>p</em>=0.025), positive lymph node metastasis (HR=2.57; 95%CI=1.49-4.43; <em>p</em><0.001), and high <em>miR-210-3p</em> expression (HR=1.82; 95%CI=1.11-2.98; <em>p</em>=0.016). Among these factors, only positive serosal invasion (HR=3.15; 95%CI=1.42-6.98; <em>p</em>=0.005) and positive lymph node metastasis (HR=2.26; 95%CI=1.31-3.92; <em>p</em>=0.004) were significant prognostic factors of RFS (<a id="xref-table-wrap-5-1" class="xref-table" href="#T5">Table V</a>).</p><div id="T5" class="table pos-float"><div class="table-inline table-callout-links"><div class="callout"><span>View this table:</span><ul class="callout-links"><li class="view-inline first"><a href="" class="table-expand-inline" data-table-url="/highwire/markup/82304/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed&table-expand-inline=1" data-icon-position="" data-hide-link-title="0">View inline</a></li><li class="view-popup"><a href="/highwire/markup/82304/expansion?width=1000&height=500&iframe=true&postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed" class="colorbox colorbox-load table-expand-popup" rel="gallery-fragment-tables" data-icon-position="" data-hide-link-title="0">View popup</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/82304" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div></div><div class="table-caption"><span class="table-label">Table V.</span> <p id="p-30" class="first-child">Prognostic factors of recurrence-free survival in 110 pancreatic ductal adenocarcinoma patients.</p><div class="sb-div caption-clear"></div></div></div><p id="p-31"><em>Expression of miR-210-3p in PDAC cell lines and siRNA/mimic transfection</em>. The expression of <em>miR-210-3p</em> was examined in 13 PDAC cell lines (<a id="xref-fig-2-1" class="xref-fig" href="#F2">Figure 2A</a>). To explore the role of <em>miR-210-3p</em> in PDAC cells, we transfected inhibition constructs into SW1990 and MiaPaca-2 cells, which showed relatively high expression levels, and mimic constructs into Capan-1 and PATU8902 cells, which exhibited relatively low expression levels. The expression of <em>miR-210-3p</em> in SW1990 and MiaPaca-2 cells was significantly down-regulated upon <em>miR-210-3p</em> inhibition, whereas the expression in Capan-1 and TU8902 was significantly up-regulated upon <em>miR-210-3p</em> mimic transfection (<a id="xref-fig-2-2" class="xref-fig" href="#F2">Figure 2B and C</a>). Cell proliferation assays revealed that <em>miR-210-3p</em> inhibition decreased cell proliferation and its over-expression increased cell proliferation (<a id="xref-fig-2-3" class="xref-fig" href="#F2">Figure 2B and C</a>).</p><div id="F2" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F2/graphic-7.large.jpg?width=800&height=600&carousel=1" title="Expression of miR-210-3p in pancreatic ductal adenocarcinoma (PDAC) cell lines and its effect on cell proliferation. A) The expression of miR-210-3p was examined in 13 PDAC cell lines. B) The miR-210-3p expression of SW1990 and MiaPaca-2 cells was significantly reduced by miR-210-3p inhibition (p=0.005, p=0.001). The proliferation of miR-210-3p knockdown cells was significantly suppressed after 24 hours (p" class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-1269938803" data-figure-caption="<div class="highwire-markup">Expression of miR-210-3p in pancreatic ductal adenocarcinoma (PDAC) cell lines and its effect on cell proliferation. A) The expression of miR-210-3p was examined in 13 PDAC cell lines. B) The miR-210-3p expression of SW1990 and MiaPaca-2 cells was significantly reduced by miR-210-3p inhibition (p=0.005, p=0.001). The proliferation of miR-210-3p knockdown cells was significantly suppressed after 24 hours (p<0.001, p<0.001). C) The miR-210-3p expression was significantly increased in Capan-1 and PATU8902 cells by miR-210-3p mimic construct transfection (p<0.001, p<0.001). The proliferation of miR-210-3p-over-expressing cells was significantly increased after 24 h (p<0.001, p<0.001).</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 2." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F2/graphic-7.medium.gif" width="333" height="440"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 2." src="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F2/graphic-7.medium.gif" width="333" height="440"/></noscript></span></a><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F2/graphic-7.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download " data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F2/graphic-7.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/82150" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F2/graphic-8.large.jpg?width=800&height=600&carousel=1" title="Expression of miR-210-3p in pancreatic ductal adenocarcinoma (PDAC) cell lines and its effect on cell proliferation. A) The expression of miR-210-3p was examined in 13 PDAC cell lines. B) The miR-210-3p expression of SW1990 and MiaPaca-2 cells was significantly reduced by miR-210-3p inhibition (p=0.005, p=0.001). The proliferation of miR-210-3p knockdown cells was significantly suppressed after 24 hours (p" class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-1269938803" data-figure-caption="<div class="highwire-markup">Expression of miR-210-3p in pancreatic ductal adenocarcinoma (PDAC) cell lines and its effect on cell proliferation. A) The expression of miR-210-3p was examined in 13 PDAC cell lines. B) The miR-210-3p expression of SW1990 and MiaPaca-2 cells was significantly reduced by miR-210-3p inhibition (p=0.005, p=0.001). The proliferation of miR-210-3p knockdown cells was significantly suppressed after 24 hours (p<0.001, p<0.001). C) The miR-210-3p expression was significantly increased in Capan-1 and PATU8902 cells by miR-210-3p mimic construct transfection (p<0.001, p<0.001). The proliferation of miR-210-3p-over-expressing cells was significantly increased after 24 h (p<0.001, p<0.001).</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 2." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F2/graphic-8.medium.gif" width="440" height="312"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 2." src="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F2/graphic-8.medium.gif" width="440" height="312"/></noscript></span></a><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F2/graphic-8.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download " data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F2/graphic-8.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/82150" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div></div></div><div class="fig-caption"><span class="fig-label">Figure 2.</span> <p id="p-32" class="first-child">Expression of miR-210-3p in pancreatic ductal adenocarcinoma (PDAC) cell lines and its effect on cell proliferation. A) The expression of miR-210-3p was examined in 13 PDAC cell lines. B) The miR-210-3p expression of SW1990 and MiaPaca-2 cells was significantly reduced by miR-210-3p inhibition (p=0.005, p=0.001). The proliferation of miR-210-3p knockdown cells was significantly suppressed after 24 hours (p<0.001, p<0.001). C) The miR-210-3p expression was significantly increased in Capan-1 and PATU8902 cells by miR-210-3p mimic construct transfection (p<0.001, p<0.001). The proliferation of miR-210-3p-over-expressing cells was significantly increased after 24 h (p<0.001, p<0.001).</p><div class="sb-div caption-clear"></div></div></div><p id="p-33">To examine the role of <em>miR-210-3p</em> in cancer cell invasion ability, we performed invasion assays. PATU8902 cells were harvested in equal numbers to each well, and either the control or mimic transfection construct was applied. We performed the assay three times, and the slides with the mimic construct showed a significantly higher number of invaded cells compared to those with the control construct (<em>p</em>=0.087). Also, MiaPaca-2 cells were harvested equally to each well, and the control or inhibition transfection construct was applied. We performed the assay four times, and the slides with the inhibition construct showed a significantly lower number of invaded cells compared to those with the control construct in two of the assays. However, the results were not consistent in the other two trials, which did not demonstrate the same findings (<em>p</em>=0.289). The representative pictures are shown in <a id="xref-fig-3-1" class="xref-fig" href="#F3">Figure 3</a>. These experiments imply that <em>miR-210-3p</em> has the potential to increase the invasive ability of cells, while <em>miR-210-3p</em> knockdown is not sufficient to decrease this ability.</p><div id="F3" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F3.large.jpg?width=800&height=600&carousel=1" title="Cell invasion assays in SW1990 and MiaPaca-2 cells. The number of invading miR-210-3p over-expressed PATU8902 cells tended to increase compared to controls. The number of invading miR-210-3p knockdown MiaPaca2 cells decreased in two experiments, while no change was observed in two other experiments compared to controls. Representative test slides are shown." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-1269938803" data-figure-caption="<div class="highwire-markup">Cell invasion assays in SW1990 and MiaPaca-2 cells. The number of invading miR-210-3p over-expressed PATU8902 cells tended to increase compared to controls. The number of invading miR-210-3p knockdown MiaPaca2 cells decreased in two experiments, while no change was observed in two other experiments compared to controls. Representative test slides are shown.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 3." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F3.medium.gif" width="440" height="248"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 3." src="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F3.medium.gif" width="440" height="248"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F3.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 3." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F3.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/82048" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption"><span class="fig-label">Figure 3.</span> <p id="p-34" class="first-child">Cell invasion assays in SW1990 and MiaPaca-2 cells. The number of invading miR-210-3p over-expressed PATU8902 cells tended to increase compared to controls. The number of invading miR-210-3p knockdown MiaPaca2 cells decreased in two experiments, while no change was observed in two other experiments compared to controls. Representative test slides are shown.</p><div class="sb-div caption-clear"></div></div></div><p id="p-35"><em>Detection of miR-210-3p targets. has-miR-210-3p</em> is localized at 11p15.5. We used the miRDB website and identified five potential target genes of <em>miR-210-3p</em>: <em>IGF2, GALR2, ISCU, KMT2D</em>, and <em>AIFM3</em> (<a id="xref-table-wrap-6-1" class="xref-table" href="#T6">Table VI</a>). Analysis of TCGA data showed that <em>ISCU</em> and <em>KMT2D</em> expression levels were significantly inversely correlated with <em>miR-210-3p</em> expression (<a id="xref-fig-4-1" class="xref-fig" href="#F4">Figure 4A</a>). FPKM was used to normalize RNA sequence data from TCGA. Since <em>ISCU</em> expression decreased significantly, we regarded it as the most relevant target gene of <em>miR-210-3p</em> in PDAC samples. We observed a significant association between <em>ISCU</em> and <em>miR-210-3p</em> expression in cDNA obtained from 55 PDAC tissues, which are part of our validation cohort. Again, <em>ISCU</em> expression was significantly lower in the high <em>miR-210-3p</em> group compared to the low <em>miR-210-3p</em> group (<em>p</em>=0.031). Western blotting analyses confirmed this trend. Additionally, knockdown of <em>miR-210-3p</em> in Mia-Paca2 cells resulted in decreased <em>ISCU</em> expression (<a id="xref-fig-4-2" class="xref-fig" href="#F4">Figure 4B</a>).</p><div id="T6" class="table pos-float"><div class="table-inline table-callout-links"><div class="callout"><span>View this table:</span><ul class="callout-links"><li class="view-inline first"><a href="" class="table-expand-inline" data-table-url="/highwire/markup/82031/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed&table-expand-inline=1" data-icon-position="" data-hide-link-title="0">View inline</a></li><li class="view-popup"><a href="/highwire/markup/82031/expansion?width=1000&height=500&iframe=true&postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed" class="colorbox colorbox-load table-expand-popup" rel="gallery-fragment-tables" data-icon-position="" data-hide-link-title="0">View popup</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/82031" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div></div><div class="table-caption"><span class="table-label">Table VI.</span> <p id="p-36" class="first-child">Target gene of miR-210-3p by miRDB.</p><div class="sb-div caption-clear"></div></div></div><div id="F4" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F4.large.jpg?width=800&height=600&carousel=1" title="Downstream target gene expression in miR-210-3p high and low expressed cases. A) Correlation between IGF2, GALR2, ISCU, KMT2, and AIFM3 and miR-210-3p in TCGA data are shown. ISCU and KMT2D showed a significant inverse correlation in TCGA Pancreatic Cancer (PAAD) from the UCSC Xena website. B) Association between ISCU and miR-210-3p in cDNA samples from 55 patients in our pancreatic ductal adenocarcinoma validation cohort. ISCU expression was significantly lower in the high miR-210-3p group compared to the low miR-210-3p group. Western blot assay also showed ISCU decrease after miR-210-3p knockdown." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-1269938803" data-figure-caption="<div class="highwire-markup">Downstream target gene expression in miR-210-3p high and low expressed cases. A) Correlation between IGF2, GALR2, ISCU, KMT2, and AIFM3 and miR-210-3p in TCGA data are shown. ISCU and KMT2D showed a significant inverse correlation in TCGA Pancreatic Cancer (PAAD) from the UCSC Xena website. B) Association between ISCU and miR-210-3p in cDNA samples from 55 patients in our pancreatic ductal adenocarcinoma validation cohort. ISCU expression was significantly lower in the high miR-210-3p group compared to the low miR-210-3p group. Western blot assay also showed ISCU decrease after miR-210-3p knockdown.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 4." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F4.medium.gif" width="416" height="440"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 4." src="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F4.medium.gif" width="416" height="440"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F4.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 4." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F4.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/82195" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption"><span class="fig-label">Figure 4.</span> <p id="p-37" class="first-child">Downstream target gene expression in miR-210-3p high and low expressed cases. A) Correlation between IGF2, GALR2, ISCU, KMT2, and AIFM3 and miR-210-3p in TCGA data are shown. ISCU and KMT2D showed a significant inverse correlation in TCGA Pancreatic Cancer (PAAD) from the UCSC Xena website. B) Association between ISCU and miR-210-3p in cDNA samples from 55 patients in our pancreatic ductal adenocarcinoma validation cohort. ISCU expression was significantly lower in the high miR-210-3p group compared to the low miR-210-3p group. Western blot assay also showed ISCU decrease after miR-210-3p knockdown.</p><div class="sb-div caption-clear"></div></div></div><p id="p-38"><em>Glycolysis stress test. ISCU</em> has been previously shown to carry a <em>miR-210-3p</em> binding site in its 3′ UTR, and is known to regulate the metabolic response (<a id="xref-ref-11-1" class="xref-bibr" href="#ref-11">11</a>, <a id="xref-ref-12-1" class="xref-bibr" href="#ref-12">12</a>). <em>ISCU</em> encodes a component of the iron-sulfur (Fe-S) cluster scaffold. Fe-S clusters are cofactors that play a role in the function of a diverse set of enzymes, including those that regulate metabolism, iron homeostasis, and oxidative stress response. <em>ISCU</em> and <em>miR-210</em> have been reported to influence the metabolism of cells by regulating mitochondrial activity (<a id="xref-ref-13-1" class="xref-bibr" href="#ref-13">13</a>). In another study on colon cancer, Ullman <em>et al.</em> showed that hypoxia up-regulates <em>miR-210-3p</em> through the activation of hypoxia-inducible factor-1α, which in turn represses <em>ISCU</em>, thereby reducing TCA cycle activity in mitochondria. As a result, L-lactate levels are elevated, and cancer stem cells initiate glycolytic activity under hypoxic conditions, which may promote cancer cell proliferation. In other words, <em>ISCU</em> reduction induces mitochondrial dysfunction (<a id="xref-ref-14-1" class="xref-bibr" href="#ref-14">14</a>). To examine whether <em>miR-210-3p</em> over-expression-induced <em>ISCU</em> reduction causes mitochondrial dysfunction, a glycolytic stress test was performed (<a id="xref-fig-5-1" class="xref-fig" href="#F5">Figure 5A, B</a>). Over-expression of <em>miR-210-3p</em> in Mia-Paca-2 cells decreased oxygen consumption (OCR) and extracellular acidification rate (ECAR). This suggests that energy metabolism is shifted from active to quiescent states as a sign of mitochondrial dysfunction. Ohsawa <em>et al.</em> report that mitochondrial dysfunction in Ras-activated cancer cells causes surrounding benign cells to exhibit metastatic behavior (<a id="xref-ref-15-1" class="xref-bibr" href="#ref-15">15</a>). From this viewpoint, mitochondrial dysfunction at the forefront of pancreatic cancer may be related to invasive characteristics.</p><div id="F5" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F5.large.jpg?width=800&height=600&carousel=1" title="Results from the glycolysis stress test using a flux analyzer on MiaPaca-2 cells. A) Knockdown of miR-210-3p increased the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). B) Whereas over-expression of miR-210-3p reduced both factors, leading to mitochondrial dysfunction." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-1269938803" data-figure-caption="<div class="highwire-markup">Results from the glycolysis stress test using a flux analyzer on MiaPaca-2 cells. A) Knockdown of miR-210-3p increased the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). B) Whereas over-expression of miR-210-3p reduced both factors, leading to mitochondrial dysfunction.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 5." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F5.medium.gif" width="307" height="440"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 5." src="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F5.medium.gif" width="307" height="440"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F5.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 5." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/44/11/4709/F5.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/82034" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption"><span class="fig-label">Figure 5.</span> <p id="p-39" class="first-child">Results from the glycolysis stress test using a flux analyzer on MiaPaca-2 cells. A) Knockdown of miR-210-3p increased the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). B) Whereas over-expression of miR-210-3p reduced both factors, leading to mitochondrial dysfunction.</p><div class="sb-div caption-clear"></div></div></div></div><div class="section discussion" id="sec-3"><h2 class="">Discussion</h2><p id="p-40">We screened miRNAs related to PDAC invasiveness and identified <em>miR-210-3p</em> as a candidate miRNA. High <em>miR-210-3p</em> expression was associated with both tumor invasiveness and poor survival outcomes in pancreatic cancers. High expression of <em>miR-210-3p</em> has been reported to be associated with poor prognosis of several epithelial cancers (<a id="xref-ref-16-1" class="xref-bibr" href="#ref-16">16</a>, <a id="xref-ref-17-1" class="xref-bibr" href="#ref-17">17</a>). For example, Ullman <em>et al.</em> showed that stable <em>miR-210</em> over-expression in colon cancer stem cells activated self-renewal activity and increased sphere formation (<a id="xref-ref-18-1" class="xref-bibr" href="#ref-18">18</a>).</p><p id="p-41">This miRNA was known to be one of the consistently up-regulated miRNAs under hypoxic conditions (<a id="xref-ref-19-1" class="xref-bibr" href="#ref-19">19</a>). Since hypoxia is known to affect the cell metabolism of PDAC, a typical hypovascular tumor, <em>miR-210-3p</em> seemed to be a relevant candidate.</p><p id="p-42">As shown in <a id="xref-table-wrap-4-2" class="xref-table" href="#T4">Table IV</a>, univariate analysis of RFS showed that high <em>miR-210-3p</em> expression was significantly associated with poor survival outcomes. Even in the subgroup analysis of cases with and without NAT, high levels of <em>miR-210-3p</em> were identified as a significant poor predictor of RFS. However, multivariate analysis showed no significant difference. this may be attributed to the role of <em>miR-210-3p</em> in influencing sensitivity to chemotherapy drugs. Li <em>et al.</em> reported that up-regulation of <em>miR-210-3p</em> elevated the sensitivity of renal cell carcinoma (RCC) to doxorubicin and vinblastine (<a id="xref-ref-20-1" class="xref-bibr" href="#ref-20">20</a>). Silakit <em>et al.</em> showed that over-expression of <em>miR-210</em> under pseudohypoxia conditions diminished gemcitabine sensitivity to cholangiocarcinoma cells (<a id="xref-ref-21-1" class="xref-bibr" href="#ref-21">21</a>). To assess the effect of <em>miR-210-3p</em> on RFS, NAT regimens should be matched between the high and low <em>miR-210-3p</em> groups.</p><p id="p-43">PDACs usually grow in a scirrhous pattern, making it difficult to achieve a visible surgical interventions. Cancer local recurrences can sometimes occur even in cases with histologically negative surgical margins (<a id="xref-ref-2-2" class="xref-bibr" href="#ref-2">2</a>). To overcome this problem, preoperative chemotherapy induction is a reasonable strategy. Our previous study revealed its effect on achieving MSM-negative status through either primary tumor shrinkage or the cessation of tumor budding (<a id="xref-ref-22-1" class="xref-bibr" href="#ref-22">22</a>). Moreover, we believe that reducing tumor invasiveness could be another effective strategy. Although <a id="xref-fig-3-2" class="xref-fig" href="#F3">Figure 3</a> indicates that the tumor-suppressing effect of knocking down a single candidate microRNA is minimal, it is important to focus on gene alterations or molecules associated with cancer invasiveness. Ohsawa <em>et al.</em> demonstrated that mitochondrial dysfunction in Ras-activated cells cooperates with Ras signaling in neighboring cells and causes tumors to express invasive characteristics (<a id="xref-ref-15-2" class="xref-bibr" href="#ref-15">15</a>). Since <em>miR-210-3p</em> correlates with mitochondrial dysfunction, its suppression may decrease tumor-invasive characteristics and enable the attainment of MSM-negative status.</p><p id="p-44">This study has several limitations, including its retrospective design and the relatively small number of cases. First, we used nucleic acid from primary cancer tissues to validate miRNA expression instead of surgical margin samples because of limited sample availability. Although detecting MSM-positivity predicting markers from the primary tumors is meaningful, our results ideally need to be confirmed using surgical margin samples. Second, the association between mitochondrial dysfunction and tumor invasiveness remains to be directly established and should be validated in future studies.</p><p id="p-45">In conclusion, <em>miR-210-3p</em> was identified as a microRNA specific to MSM-positive cases using primary PDAC surgical specimens. Increased <em>miR-210-3p</em> expression induces mitochondrial dysfunction through the reduction of <em>ISCU</em>, which may contribute to tumor invasiveness and poor postoperative RFS.</p></div><div class="section ack" id="ack-1"><h2 class="">Acknowledgements</h2><p id="p-50">The Authors thank Gabrielle White Wolf, PhD, from Edanz (<a href="https://jp.edanz.com/ac">https://jp.edanz.com/ac</a>) for editing a draft of this manuscript.</p></div><div class="section fn-group" id="fn-group-1"><h2>Footnotes</h2><ul><li class="fn" id="fn-1"><p id="p-1"><strong>Authors’ Contributions</strong></p><p id="p-2">M.H. designed the project. D.K., M.H., and T.O. collected clinical data and analyzed them. D.K., T.O., K.F., and M.H. conducted cell experiments. T.O., M.H. and K.F. wrote the article. M.H., N.N., K.K., H.T., K.N., S.U., D.S., N.H., M.K., C.T., G.N. and Y.K. critically reviewed the article.</p></li><li class="fn" id="fn-2"><p id="p-46"><strong>Conflicts of Interest</strong></p><p id="p-47">The Authors have no conflicts of interest to declare in relation to this study.</p></li><li class="fn" id="fn-3"><p id="p-48"><strong>Funding</strong></p><p id="p-49">This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Research Activity Start-up number 15H06281 and Grant in Aid for Scientific Research (C)21K07147.</p></li></ul></div><ul class="history-list"><li xmlns:hwp="http://schema.highwire.org/Journal" class="received" hwp:start="2024-09-17"><span class="received-label">Received </span>September 17, 2024.</li><li xmlns:hwp="http://schema.highwire.org/Journal" class="rev-recd" hwp:start="2024-10-04"><span class="rev-recd-label">Revision received </span>October 4, 2024.</li><li xmlns:hwp="http://schema.highwire.org/Journal" class="accepted" hwp:start="2024-10-07"><span class="accepted-label">Accepted </span>October 7, 2024.</li></ul><ul class="copyright-statement"><li class="fn" id="copyright-statement-1">Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.</li></ul><div class="license" id="license-1"><p id="p-3">This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (<a href="https://creativecommons.org/licenses/by-nc-nd/4.0" rel="license">https://creativecommons.org/licenses/by-nc-nd/4.0</a>).</p></div><div class="section ref-list" id="ref-list-1"><h2 class="">References</h2><ol class="cit-list"><li><a class="rev-xref-ref" href="#xref-ref-1-1" title="View reference 1 in text" id="ref-1">↵</a><div class="cit ref-cit ref-journal" id="cit-44.11.4709.1" data-doi="10.3322/caac.21763"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Siegel</span> <span class="cit-name-given-names">RL</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Miller</span> <span class="cit-name-given-names">KD</span></span>, </li><li><span 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class="cit-name-surname">Nakayama</span> <span class="cit-name-given-names">G</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Koike</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kodera</span> <span class="cit-name-given-names">Y</span></span></li></ol><cite>: <span class="cit-article-title">Impact of molecular surgical margin analysis on the prediction of pancreatic cancer recurrences after pancreaticoduodenectomy</span>. <abbr class="cit-jnl-abbrev">Clin Epigenetics</abbr> <span class="cit-vol">13</span>(<span class="cit-issue">1</span>): <span class="cit-fpage">172</span>, <span class="cit-pub-date">2021</span>.<span class="cit-pub-id-sep cit-pub-id-doi-sep"> </span><span class="cit-pub-id-scheme">DOI: </span><span class="cit-pub-id cit-pub-id-doi">10.1186/s13148-021-01165-8</span></cite></div><div class="cit-extra"><a 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class="panel-pane pane-highwire-article-citation large-margin-bottom" > <div class="pane-content"> <div class="highwire-article-citation highwire-citation-type-highwire-article node82128--3" data-node-nid="82128" id="share-node-82128--41729548032" data-pisa="anticanres;44/11/4709" data-pisa-master="anticanres;44/11/4709" data-apath="/anticanres/44/11/4709.atom"><div class="highwire-cite highwire-cite-highwire-article highwire-citation-jcore-standard clearfix"> <div class="highwire-cite-title">Genome-wide microRNA Analysis Identified <em>miR-210-3p</em> Over-expression in Pancreatic Cancer Tissues as a Predictor of their Local Invasiveness</div> <div class="highwire-cite-authors"><span class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0"><span class="nlm-given-names">TOMOHISA</span> <span class="nlm-surname">OTSU</span></span>, <span class="highwire-citation-author" data-delta="1"><span class="nlm-given-names">MASAMICHI</span> <span class="nlm-surname">HAYASHI</span></span>, <span class="highwire-citation-author" data-delta="2"><span class="nlm-given-names">KEIZO</span> <span class="nlm-surname">FUJITA</span></span>, <span class="highwire-citation-author" data-delta="3"><span class="nlm-given-names">DAIGO</span> <span class="nlm-surname">KOBAYASHI</span></span>, <span class="highwire-citation-author" data-delta="4"><span class="nlm-given-names">NOBUHIKO</span> <span class="nlm-surname">NAKAGAWA</span></span>, <span class="highwire-citation-author" data-delta="5"><span class="nlm-given-names">KEISUKE</span> <span class="nlm-surname">KURIMOTO</span></span>, <span class="highwire-citation-author" data-delta="6"><span class="nlm-given-names">HIDEKI</span> <span class="nlm-surname">TAKAMI</span></span>, <span class="highwire-citation-author" data-delta="7"><span class="nlm-given-names">KOKI</span> <span class="nlm-surname">NAKANISHI</span></span>, <span class="highwire-citation-author" data-delta="8"><span class="nlm-given-names">SHINICHI</span> <span class="nlm-surname">UMEDA</span></span>, <span class="highwire-citation-author" data-delta="9"><span class="nlm-given-names">DAI</span> <span class="nlm-surname">SHIMIZU</span></span>, <span class="highwire-citation-author" data-delta="10"><span class="nlm-given-names">NORIFUMI</span> <span class="nlm-surname">HATTORI</span></span>, <span class="highwire-citation-author" data-delta="11"><span class="nlm-given-names">MITSURO</span> <span class="nlm-surname">KANDA</span></span>, <span class="highwire-citation-author" data-delta="12"><span class="nlm-given-names">CHIE</span> <span class="nlm-surname">TANAKA</span></span>, <span class="highwire-citation-author" data-delta="13"><span class="nlm-given-names">GORO</span> <span class="nlm-surname">NAKAYAMA</span></span>, <span class="highwire-citation-author" data-delta="14"><span class="nlm-given-names">YASUHIRO</span> <span class="nlm-surname">KODERA</span></span></span></div> <div class="highwire-cite-metadata"><span class="highwire-cite-metadata-oa-ind highwire-cite-metadata"><i class="highwire-oa-indicator"></i> </span><span class="highwire-cite-metadata-journal highwire-cite-metadata">Anticancer Research </span><span class="highwire-cite-metadata-date highwire-cite-metadata">Nov 2024, </span><span class="highwire-cite-metadata-volume highwire-cite-metadata">44 </span><span class="highwire-cite-metadata-issue highwire-cite-metadata">(11) </span><span class="highwire-cite-metadata-pages highwire-cite-metadata">4709-4721; </span><span class="highwire-cite-metadata-doi highwire-cite-metadata"><span class="label">DOI:</span> 10.21873/anticanres.17297 </span></div> </div> </div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-article-clipboard-copy large-margin-bottom" > <div class="pane-content"> <div class = "clipboard-copy"> <span class="label-url"> <label for="dynamic">Share This Article:</label> </span> <span 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