{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T01:48:04Z","timestamp":1783648084449,"version":"3.55.0"},"reference-count":66,"publisher":"National Academy of Sciences","issue":"48","license":[{"start":{"date-parts":[[2019,11,8]],"date-time":"2019-11-08T00:00:00Z","timestamp":1573171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["31003A_166358"],"award-info":[{"award-number":["31003A_166358"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,11,26]]},"abstract":"<jats:p>\n                    MicroRNA-mediated gene regulation has been implicated in various diseases, including cancer. This study examined the role of microRNAs (miRNAs) during tumorigenesis and malignant progression of pancreatic neuroendocrine tumors (PanNETs) in a genetically engineered mouse model. Previously, a set of miRNAs was observed to be specifically up-regulated in a highly invasive and metastatic subtype of mouse and human PanNET. Using functional assays, we now implicate different miRNAs in distinct phenotypes: miR-137 stimulates tumor growth and local invasion, whereas the miR-23b cluster enables metastasis. An algorithm, Bio-miRTa, has been developed to facilitate the identification of biologically relevant miRNA target genes and applied to these miRNAs. We show that a top-ranked miR-137 candidate gene,\n                    <jats:italic>Sorl1<\/jats:italic>\n                    , has a tumor suppressor function in primary PanNETs. Among the top targets for the miR-23b cluster,\n                    <jats:italic>Acvr1c\/ALK7<\/jats:italic>\n                    has recently been described to be a metastasis suppressor, and we establish herein that it is down-regulated by the miR-23b cluster, which is crucial for its prometastatic activity. Two other miR-23b targets,\n                    <jats:italic>Robo2<\/jats:italic>\n                    and\n                    <jats:italic>P2ry1<\/jats:italic>\n                    , also have demonstrable antimetastatic effects. Finally, we have used the Bio-miRTa algorithm in reverse to identify candidate miRNAs that might regulate activin B, the principal ligand for ALK7, identifying thereby a third family of miRNAs\u2014miRNA-130\/301\u2014that is congruently up-regulated concomitant with down-regulation of activin B during tumorigenesis, suggestive of functional involvement in evasion of the proapoptotic barrier. Thus, dynamic up-regulation of miRNAs during multistep tumorigenesis and malignant progression serves to down-regulate distinctive suppressor mechanisms of tumor growth, invasion, and metastasis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1913307116","type":"journal-article","created":{"date-parts":[[2019,11,8]],"date-time":"2019-11-08T20:59:17Z","timestamp":1573246757000},"page":"24184-24195","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":50,"title":["A set of microRNAs coordinately controls tumorigenesis, invasion, and metastasis"],"prefix":"10.1073","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7674-1233","authenticated-orcid":false,"given":"Iacovos P.","family":"Michael","sequence":"first","affiliation":[{"name":"Swiss Institute for Experimental Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology Lausanne, 1015 Lausanne, Switzerland;"},{"name":"Swiss Cancer Center Leman, 1015 Lausanne, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadegh","family":"Saghafinia","sequence":"additional","affiliation":[{"name":"Swiss Institute for Experimental Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology Lausanne, 1015 Lausanne, Switzerland;"},{"name":"Swiss Cancer Center Leman, 1015 Lausanne, Switzerland;"},{"name":"Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Hanahan","sequence":"additional","affiliation":[{"name":"Swiss Institute for Experimental Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology Lausanne, 1015 Lausanne, Switzerland;"},{"name":"Swiss Cancer Center Leman, 1015 Lausanne, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,11,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nrc.2016.25","article-title":"Targeting metastasis","volume":"16","author":"Steeg P. 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