LAUSR

Background and Significance: Non-alcoholic fatty liver disease (NAFLD) is a major risk factor for the development of hepatocellular carcinoma (HCC). Even with successful surgical removal, the presence of NAFLD is associated with an increased recurrence of HCC. Despite the apparent association between NAFLD and HCC, the mechanistic pathways that link both disorders are essentially unknown and therapeutic agents for both disorders are lacking. MicroRNAs (miRNAs) play critical roles in both cancer and metabolic disorders, and present tremendous therapeutic potential. Methods: We used four mouse models including ATK/Ras HCC mice, cMyc HCC mice, xenograft HCC mice and dietary obese mice to evaluate the therapeutic effects of miR-206 on the pathogenesis of HCC and NAFLD. Mini-circle and Sleeping Beauty system were used to deliver miR-206 into livers of mice. Results: miRNA profiling revealed that hepatic fat accumulation impaired biogenesis of miR-206 that is also robustly under-expressed in livers of HCC mice and HCC patients. System administration of miR-206 completely prevented HCC development in both cMyc and AKT/Ras HCC mice, while 100% control mice died from lethal tumor burdens. Upon dissection, no tumor nodules were observed in livers of both AKT/Ras and cMyc mice treated with miR-206. Notably, liver-specific expression of miR-206 displayed the robust therapeutic effects on obesity and NAFLD in dietary obese mice and delivery of miR-206 into human hepatocytes significantly reduced intracellular lipid content. Combining bioinformatic prediction and molecular and cellular approaches, we identified cMet (Met proto-oncogene), CCND1, CDK4/6, EGFR, and PTPN1 (protein tyrosine phosphatase 1B) as essential direct targets of miR-206. It is known that PTPN1 can dephosphorylate PP2A (phosphatase 2A). Dephosphorylated PP2A (active form) can activate transcription of Srebp1c by dephosphorylating Sp1, a transcription activator of Srebp1c. As expected, through modulating PTPN1-PP2A-SP1-Srebp1c axis, miR-206 impaired Srebp1c-mediated lipogenesis in livers of dietary obese mice and in human hepatocytes treated with a fatty acid, while the prevention of the interaction between miR-206 and PTPN1 offset the inhibitory effects of miR-206 on lipogenesis and hepatic lipid accumulation in vivo and in vitro, suggesting that PTPN1 mediates the therapeutic effects of miR-206 on NAFLD. Through inhibiting expression of cMet, CCND1, CDK4/6, and EGFR, miR-206 completely prevented colony formation of HCC cell lines with divergent backgrounds and growth of xenograft HCC tumor from different HCC cells by impairing cMet signaling, EGFR signaling and cell cycle progression. Conclusion: This defines a critical role of miR-206 in preventing the pathogenesis of highly-associated NAFLD and HCC, and suggests its strong potential as a therapeutic strategy for both disorders. Citation Format: Guisheng Song, Heng Wu, Junyan Tao, Xin Chen. microRNA-206 as a potential therapeutic approach for highly-associated NAFLD and HCC. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A18.