The lncRNA H19 is pro-oncogenic in chronic inflammation-mediated hepatocellular carcinoma

H19 is paternally imprinted, maternally expressed oncofetal long non-coding RNA (lncRNA), which is repressed at birth in most tissues, and is re-expressed in many cancers, including hepatocellular carcinoma (HCC). The role of H19 in carcinogenesis is controversial. We aimed to examine the role of H19 in chronic inflammation-mediated hepatocarcinogenesis using the Mdr2/Abcb4 knock-out (Mdr2-KO) mouse, a well-established model of chronic cholangitis and hepatitis culminating in HCC development. We have combined the Mdr2-KO and H19-KO mutations in the C57BL/6 strain, and followed spontaneous tumor development in the generated double knock-out (dKO) and control Mdr2-KO mice. Tumor incidence and tumor load were both significantly decreased in the liver of dKO vs. Mdr2-KO females. Hepatocyte proliferation was decreased in the non-tumor liver tissue of dKO vs. Mdr2-KO females. Single-molecule RNA-FISH demonstrated that H19 was expressed in a small fraction of hepatocytes which appeared sporadically, mainly in the zone 2. At early age, dKO vs. Mdr2-KO females had lower level of liver injury and higher percentage of binuclear hepatocytes, which have a tumor-suppressive role in the liver. Transcriptome profiling revealed that livers of dKO vs. Mdr2-KO females were characterized by a reduced expression of inflammatory response and EMT markers. In HCC patients, H19 expression was higher in females, positively correlated with cirrhosis (in non-tumor samples) and negatively correlated with mutated CTNNB1 gene encoding beta-catenin (in tumors). Our results demonstrate that the total effect of lncRNA H19 in the development of chronic inflammation-mediated HCC in this model is not tumor suppressive, but rather pro-oncogenic.