The oncofetal long noncoding RNA (lncRNA) H19 is postnatally repressed in most tissues, and re-expressed in many cancers, including hepatocellular carcinoma (HCC). The role of H19 in carcinogenesis is a subject of controversy. We aimed to examine the role of H19 in chronic inflammation-mediated hepatocarcinogenesis using the Mdr2/Abcb4 knockout (Mdr2-KO) mouse, a well-established HCC model. For this goal, we have generated Mdr2-KO/H19-KO double knockout (dKO) mice and followed spontaneous tumor development in the dKO and control Mdr2-KO mice. Cellular localization of H19 and effects of H19 loss in the liver were determined in young and old Mdr2-KO mice. Tumor incidence and tumor load were both significantly decreased in the liver of dKO versus Mdr2-KO females. The expression levels of H19 and Igf2 were variable in nontumor liver tissues of Mdr2-KO females and were significantly downregulated in most matched tumors. In nontumor liver tissue of aged Mdr2-KO females, H19 was expressed mainly in hepatocytes, and hepatocyte proliferation was increased compared to dKO females. At an early age, dKO females displayed lower levels of liver injury and B-cell infiltration, with higher percentage of binuclear hepatocytes. In human samples, H19 expression was higher in females, positively correlated with cirrhosis (in nontumor liver samples) and negatively correlated with CTNNB1 (beta-catenin) mutations and patients’ survival (in tumors). Our data demonstrate that the lncRNA H19 is pro-oncogenic during the development of chronic inflammation-mediated HCC in the Mdr2-KO mouse model, mainly by increasing liver injury and decreasing hepatocyte polyploidy in young mice.
Bibliographical noteFunding Information:
Funding Robert H. Benson Living Trust and Selma Kron Foundation to student fellowships. DSG is supported by the Kamea Scientific Foundation of the Israeli Government. JHA was supported by ISF 923/ 14. SC was supported by a funding from Labex OncoImunology and CARPEM. The JZR group was supported by INSERM, Ligue Nationale contre le Cancer (Equipe Labellisée), Labex OncoImmu-nology (investissement d’avenir), grant IREB, Coup d’Elan de la Fondation Bettencourt-Schueller, the SIRIC CARPEM, Raymond Rosen Award from the Fondation pour le Recherche Médicale, Prix René and Andrée Duquesne—Comité de Paris Ligue Contre le Cancer and Fondation Mérieux. The work of EG was supported by the: ERC advance—GA No. 786575—RxmiRcanceR, Deutsche For-schungsgemeinschaft (DFG) SFB841 project C3, NIH CA197081-02, MOST, ISF collaboration with Canada (2473/2017), personal ISF (486/2017), ICORE–ISF (41/2011), and by DKFZ-MOST.
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