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Here we investigated the role of OSM in the development and progression of hepatocellular carcinoma (HCC) in non\u2010alcoholic fatty liver disease (NAFLD)\/non\u2010alcoholic steatohepatitis (NASH). The role of OSM was investigated in (1) selected cohorts of NAFLD\/NASH HCC patients, (2) liver cancer cells exposed to human recombinant OSM or stably transfected to overexpress human OSM, (3) murine HCC xenografts, and (4) a murine NASH\u2010related model of hepatic carcinogenesis. OSM was found to be selectively overexpressed in HCC cells of NAFLD\/NASH patients, depending on tumor grade. OSM serum levels, barely detectable in patients with simple steatosis or NASH, were increased in patients with cirrhosis and more evident in those carrying HCC. In this latter group, OSM serum levels were significantly higher in the subjects with intermediate\/advanced HCCs and correlated with poor survival. Cell culture experiments indicated that OSM upregulation in hepatic cancer cells contributes to HCC progression by inducing epithelial\u2010to\u2010mesenchymal transition and increased invasiveness of cancer cells as well as by inducing angiogenesis, which is of critical relevance. In murine xenografts, OSM overexpression was associated with slower tumor growth but an increased rate of lung metastases. Overexpression of OSM and its positive correlation with the angiogenic switch were also confirmed in a murine model of NAFLD\/NASH\u2010related hepatocarcinogenesis. Consistent with this, analysis of liver specimens from human NASH\u2010related HCCs with vascular invasion showed that OSM was expressed by liver cancer cells invading hepatic vessels. In conclusion, OSM upregulation appears to be a specific feature of HCC arising on a NAFLD\/NASH background, and it correlates with clinical parameters and disease outcome. Our data highlight a novel pro\u2010carcinogenic contribution for OSM in NAFLD\/NASH, suggesting a role of this factor as a prognostic marker and a putative potential target for therapy. \u00a9 2022 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.5871","type":"journal-article","created":{"date-parts":[[2022,1,22]],"date-time":"2022-01-22T04:33:48Z","timestamp":1642826028000},"page":"82-95","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Oncostatin <scp>M<\/scp> is overexpressed in <scp>NASH<\/scp>\u2010related hepatocellular carcinoma and promotes cancer cell invasiveness and angiogenesis"],"prefix":"10.1002","volume":"257","author":[{"given":"Giovanni","family":"Di Maira","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental 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