{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:48:38Z","timestamp":1787064518136,"version":"build-2736575974"},"reference-count":36,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T00:00:00Z","timestamp":1631664000000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81974053"],"award-info":[{"award-number":["81974053"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Esophageal squamous cell carcinoma (ESCC) is a highly aggressive and treatment\u2010resistant tumor. The biological implications and molecular mechanism of cancer stem\u2010like cells (CSCs) in ESCC, which contribute to therapeutic resistance such as radioresistance, remain elusive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Quantitative real\u2010time polymerase chain reaction, western blotting, immunohistochemistry, and in situ hybridization assays were used to detect methyltransferase\u2010like 14 miR\u201099a\u20105p tribble 2 (METTL14\/miR\u201099a\u20105p\/TRIB2) expression in ESCC. The biological functions of METTL14\/miR\u201099a\u20105p\/TRIB2 were demonstrated in vitro and in vivo. Mass spectrum analysis was used to identify the downstream proteins regulated by TRIB2. Chromatin immunoprecipitation (IP), IP, N\n                      <jats:sup>6<\/jats:sup>\n                      \u2010methyladenosine (m\n                      <jats:sup>6<\/jats:sup>\n                      A)\u2010RNA IP, luciferase reporter, and ubiquitination assays were employed to explore the molecular mechanisms underlying this feedback circuit and its downstream pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that miR\u201099a\u20105p was significantly decreased in ESCC. miR\u201099a\u20105p inhibited CSCs persistence and the radioresistance of ESCC cells, and miR\u201099a\u20105p downregulation predicted an unfavorable prognosis of ESCC patients. Mechanically, we unveiled a METTL14\u2010miR\u201099a\u20105p\u2010TRIB2 positive feedback loop that enhances CSC properties and radioresistance of ESCC cells. METTL14, an m\n                      <jats:sup>6<\/jats:sup>\n                      A RNA methyltransferase downregulated in ESCC, suppresses TRIB2 expression via miR\u201099a\u20105p\u2010mediated degradation of TRIB2 mRNA by targeting its 3\u2032 untranslated region, whereas TRIB2 induces ubiquitin\u2010mediated proteasomal degradation of METTL14 in a COP1\u2010dependent manner. METTL14 upregulates miR\u201099a\u20105p by modulating m\n                      <jats:sup>6<\/jats:sup>\n                      A\u2010mediated, DiGeorge critical region 8\u2010dependent pri\u2010mir\u201099a processing. Hyperactivation of TRIB2 resulting from this positive circuit was closely correlated with radioresistance and CSC characteristics. Furthermore, TRIB2 activates HDAC2 and subsequently induces p21 epigenetic repression through Akt\/mTOR\/S6K1 signaling pathway activation. Pharmacologic inhibition of HDAC2 effectively attenuates the TRIB2\u2010mediated effect both in vitro and in patient\u2010derived xenograft models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our data highlight the presence of the METTL14\/miR\u201099a\u20105p\/TRIB2 axis and show that it is positively associated with CSC characteristics and radioresistance of ESCC, suggesting potential therapeutic targets for ESCC treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.545","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T03:28:23Z","timestamp":1631676503000},"source":"Crossref","is-referenced-by-count":69,"title":["A methyltransferase\u2010like 14\/miR\u201099a\u20105p\/tribble 2 positive feedback circuit promotes cancer stem cell persistence and radioresistance via histone deacetylase 2\u2010mediated epigenetic modulation in esophageal squamous cell carcinoma"],"prefix":"10.1002","volume":"11","author":[{"given":"Zhenchuan","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, Shanghai Tongji Hospital, School of Medicine Tongji University  Shanghai P.R. 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