Reactivation of telomerase reverse transcriptase gene in liver cancer

Abstract

Hepatocellular Carcinoma (HCC) is one of the major causes of cancer related deaths worldwide and its incidence has been increasing drastically, especially in western countries. HCC has a heterogeneous molecular and pathological background with various underlying risk factors and survival rate of HCC patients is very low due to late diagnosis and limited curative therapies. The mechanisms involved in hepatocellular immortality gains critical importance in order to develop preventive and therapeutic options against HCC. Telomerase reactivation is a keystone for HCC cells during transformation process. TERT promoter mutations activating its promoter by creating a novel activating motif were recently identified in different cancer types. In this study; we determined TERT promoter mutation frequency in HCC cell lines and tumors which are 67% (10/15) and 34% (15/44) respectively. High frequency of TERT promoter mutations in HCC indicated a possible functional role during hepatocarcinogenesis. We performed transcriptional factor search to find a candidate TF that could bind to mutant TERT promoter and STAT1 came out of that search. To study the role of STAT1 during reactivation of TERT expression, we activated STAT1 signaling by Interferon alpha (IFN-α) treatment and down regulated STAT1 with RNA interference in several HCC cell lines. We have found that IFN-α was able to upregulate TERT expression in the HCC cell lines carrying a TERT promoter mutation and STAT1 knockdown was enough to eradicate this upregulation. In case of wild type cell lines, IFN-α treatment and STAT1 knock down had no effect on TERT expression. Our data delineates the contributions of TERT promoter mutations to hepatocellular immortality and gives insights into the potential use of TERT as a target for chemoprevention of hepatocarcinogenesis.