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Obesity and inflammation are risk factors for hepatocellular carcinoma, however, the role of Nod2 in obesity-dependent hepatic tumorigenesis is not known. Here we tested the hypothesis that <jats:italic>Nod2<\/jats:italic> protects from high fat diet (HFD)-dependent hepatic cancer. We used an obesity-dependent hepatic tumor model. WT and <jats:italic>Nod2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice were treated with the carcinogen dimethylbenz[a]anthracene (DMBA) and maintained on HFD. <jats:italic>Nod2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice treated with DMBA and maintained on HFD gain significantly more weight and develop more liver tumors than similarly treated WT mice. Livers of <jats:italic>Nod2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> tumorigenic mice had increased expression of genes involved in cell proliferation, immune responses, and cholesterol biosynthesis, increased infiltration of neutrophils, inflammatory monocytes, and T cells, and increased activation of STAT3 and ERK during the later stages of tumorigenesis. Bioinformatic analyses of genes with differential expression predicted an increase in cancer, immune, and cholesterol biosynthesis pathways. In summary, we have identified a novel role for <jats:italic>Nod2<\/jats:italic> and demonstrate that <jats:italic>Nod2<\/jats:italic> protects from HFD-dependent liver malignancy and this protection is accompanied by decreased cell proliferation, inflammation, steroid biosynthesis, neutrophils and macrophages infiltration, and STAT3 and MAPK signaling in the liver.<\/jats:p>","DOI":"10.1038\/s41598-020-77463-7","type":"journal-article","created":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T11:03:44Z","timestamp":1606302224000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Nod2 protects mice from inflammation and obesity-dependent liver cancer"],"prefix":"10.1038","volume":"10","author":[{"given":"Serdar A.","family":"Gurses","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunil","family":"Banskar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cody","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bill","family":"Trimoski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Dziarski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dipika","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,25]]},"reference":[{"key":"77463_CR1","doi-asserted-by":"publisher","first-page":"2494","DOI":"10.3748\/wjg.v22.i8.2494","volume":"22","author":"B Charrez","year":"2016","unstructured":"Charrez, B., Qiao, L. & Hebbard, L. 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