Hepatocyte nuclear factor 4 alpha deletion promotes diethylnitrosamine-induced hepatocellular carcinoma in rodents

• DOI: 10.1002/hep.26251
• Publication Date: 2013-01-12T12:28:52Z
• Authors: Chad Walesky; Genea Edwards; Prachi Borude; Sumedha Gunewardena; Maura O'Neil; Byunggil Yoo; Udayan Apte
• Keywords: Hepatocyte nuclear factors; Liver Cancer

Hepatocyte nuclear factor 4 alpha (HNF4α), the master regulator of hepatocyte differentiation, has been recently shown to inhibit proliferation by way unknown mechanisms. We investigated mechanisms HNF4α-induced inhibition using a novel tamoxifen (TAM)-inducible, hepatocyte-specific HNF4α knockdown mouse model. Hepatocyte-specific deletion in adult mice resulted increased proliferation, with significant increase liver-to-body-weight ratio. determined global gene expression changes Illumina HiSeq-based RNA sequencing, which revealed that number up-regulated genes following were associated cancer pathogenesis, cell cycle control, and proliferation. The pathway analysis further c-Myc-regulated network was highly activated deletion. To determine whether affects induced treated known hepatic carcinogen diethylnitrosamine (DEN). Deletion significantly size DEN-induced tumors. Pathological tumors HNF4α-deleted well-differentiated hepatocellular carcinoma (HCC) mixed HCC-cholangiocarcinoma. Analysis surrounding normal liver tissue DEN-treated knockout showed induction c-Myc expression. Taken together, hepatocytes results promotion secondary aberrant activation.