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However, the underlying mechanism by which hepatic inflammation progresses to HCC is poorly understood. This study was designed to investigate the role of ETS translocation variant 4 (ETV4) in linking hepatic inflammation to HCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Quantitative real\u2010time PCR and immunoblotting were used to detect the expression of ETV4 in HCC tissues and cell lines. RNA sequencing and luciferase reporter assays were performed to identify the target genes of ETV4. Hepatocyte\u2010specific\n                      <jats:italic toggle=\"yes\">ETV4<\/jats:italic>\n                      \u2010knockout (\n                      <jats:italic toggle=\"yes\">ETV4<\/jats:italic>\n                      <jats:sup>fl\/fl, alb\u2010cre<\/jats:sup>\n                      ) and transgenic (\n                      <jats:italic toggle=\"yes\">ETV4<\/jats:italic>\n                      <jats:sup>Hep\u2010TG<\/jats:sup>\n                      ) mice and diethylnitrosamine\u2010carbon tetrachloride (DEN\u2010CCL\n                      <jats:sub>4<\/jats:sub>\n                      ) treatment experiments were applied to investigate the function of ETV4 in\n                      <jats:italic toggle=\"yes\">vivo<\/jats:italic>\n                      . The Cancer Genome Atlas (TCGA) database mining and pathological analysis were carried out to determine the correlation of ETV4 with tumor necrosis factor\u2010alpha (TNF\u2010\u03b1) and mitogen\u2010activated protein kinase 11 (MAPK11).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      We revealed that ETV4 was highly expressed in HCC. High levels of ETV4 predicted a poor survival rate of HCC patients. Then we identified ETV4 as a transcription activator of TNF\u2010\u03b1 and MAPK11. ETV4 was positively correlated with TNF\u2010\u03b1 and MAPK11 in HCC patients. As expected, an increase in hepatic TNF\u2010\u03b1 secretion and macrophage accumulation were observed in the livers of\n                      <jats:italic toggle=\"yes\">ETV4<\/jats:italic>\n                      <jats:sup>Hep\u2010TG<\/jats:sup>\n                      mice. The protein levels of TNF\u2010\u03b1, MAPK11, and CD68 were significantly higher in the livers of\n                      <jats:italic toggle=\"yes\">ETV4<\/jats:italic>\n                      <jats:sup>Hep\u2010TG<\/jats:sup>\n                      mice compared with wild type mice but lower in\n                      <jats:italic toggle=\"yes\">ETV4<\/jats:italic>\n                      <jats:sup>fl\/fl, alb\u2010cre<\/jats:sup>\n                      mice compared with\n                      <jats:italic toggle=\"yes\">ETV4<\/jats:italic>\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      mice as treated with DEN\u2010CCL\n                      <jats:sub>4<\/jats:sub>\n                      , indicating that ETV4 functioned as a driver of TNF\u2010\u03b1\/MAPK11 expression and macrophage accumulation during hepatic inflammation. Hepatocyte\u2010specific knockout of ETV4 significantly prevented development of DEN\u2010CCL\n                      <jats:sub>4<\/jats:sub>\n                      \u2010induced HCC, while transgenic expression of ETV4 promoted growth of HCC.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">ETV4 promoted hepatic inflammation and HCC by activating transcription of TNF\u2010\u03b1 and MAPK11. Both the ETV4\/TNF\u2010\u03b1 and ETV4\/MAPK11 axes represented two potential therapeutic targets for highly associated hepatic inflammation and HCC. ETV4+TNF\u2010\u03b1 were potential prognostic markers for HCC patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cac2.12482","type":"journal-article","created":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T01:53:25Z","timestamp":1693965205000},"page":"1354-1372","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Transcription factor ETV4 promotes the development of hepatocellular carcinoma by driving hepatic TNF\u2010\u03b1 signaling"],"prefix":"10.34133","volume":"43","author":[{"given":"Dandan","family":"Qi","sequence":"first","affiliation":[{"name":"Institute of Microbiology, Chinese Academy of Sciences","place":["Beijing, P. R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Lu","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, Chinese Academy of Sciences","place":["Beijing, P. R. 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