Hepatitis C virus core protein enhances Telomerase activity in Huh7 cells

Abstract

Hepatitis C is an oncogenic virus although the mechanisms responsible for this behavior are not clear. We studied the effects of hepatitis C virus (HCV) core protein expression on Telomerase, an enzyme closely associated with cellular immortalization and neoplasia. The aim of this study was to investigate the effects of HCV core protein on the regulation of Telomerase activity in human hepatoma cells. Regulation and expression of human Telomerase reverse transcriptase (TERT) was compared in Huh7 cells stably transfected with HCV core protein or cells expressing vector alone. Telomerase activity was measured using Quantitative Telomerase Detection (QTD) and telomere length was measured by fluorescence in situ hybridization (FISH). Transient transfection and luciferase assay were used to evaluate TERT promoter activity. Telomerase activity was increased twofold in Huh7 cells expressing HCV core protein compared to controls (P < 0.01). This was accompanied by a 1.4-fold increase of TERT mRNA and 1.9-fold increase in TERT protein (P < 0.01 in either case). Cellular fractionation and immunocytochemical studies showed increased localization of TERT in the nucleus of core-expressing cells as compared to controls. FISH assay confirmed that telomeres of HCV core-expressing Huh7 cells were relatively longer than those of control cells (0.22 + 0.05 vs. 0.12 + 0.03, P < 0.01). TERT promoter activity was enhanced about 30% in HCV core-expressing Huh7 cells compared to control cells (P < 0.02). HCV core protein is associated with increased Telomerase activity in hepatoma cells. These findings suggest that enhancement of Telomerase activity by HCV core protein may contribute to the oncogenicity of HCV.

Ageing, telomeres, senescence, and liver injury

“…Recent data have demonstrated a similar effect of HCV proteins upon telomerase activity. Zhu et al demonstrated a twofold increase in telomerase activity in Huh7 cells expressing HCV core protein compared to mock transfected cells [122]. There were detectable increases in telomerase mRNA, protein, and promoter activity; these changes were associated with significantly longer telomere length in cells expressing HCV core, suggesting functional telomerase activity.…”

The correlation between iron homeostasis and telomere maintenance

“…A variety of studies have indicated that telomerase activity is markedly increased either in iron overload or iron deficient condition (Brown et al, 2007;Zhu et al, 2010;Mainous et al, 2013). In human, mutations in TERT have been implicated in predisposing patients to aplastic anemia, a disorder in which the bone marrow fails to produce blood cells (Calado and Young, 2012).…”

A second chance for telomerase reverse transcriptase in anticancer immunotherapy

“…TERT-promoter mutations prevent silencing of the TERT gene, increasing its transcription; although TERT-protein expression might not be directly proportional to the level of heightened transcription 157 , even a twofold increase in TERT levels would generate more peptides, potentially making tumour TERT-based immunotherapy. Of relevance, in humans the TERT promoter is a common integration site for several viruses, including hepatitis B virus 153,154 , hepatitis C virus 155 , and human papillomavirus 156 -which can lead to activation of the TERT gene in cis.…”