Abstract
Inevitable long-term therapy with nucleos(t)ide analogs in patients with chronic hepatitis B virus (HBV) infection has selected reverse-transcriptase (rt) mutants in a substantial proportion of patients. Some of these mutants introduce premature stop codons in the overlapping surface (s) gene, including rtA181T/sW172*, which has been shown to enhance oncogenicity. The oncogenicity of another drug-resistant mutant, rtM204I/sW196*, has not been studied. We constructed plasmids harboring rtM204I/sW196* and assessed the in vitro cell transformation, endoplasmic reticulum (ER) stress response, and xenograft tumorigenesis of the transformants. Cellular gene expression was analyzed by cDNA microarray and was validated. The rtM204I/sW196* transformants, compared with the control or wild type, showed enhanced transactivation activities for c-fos, increased cell proliferation, decreased apoptosis, more anchorage-independent growth, and enhanced tumor growth in mouse xenografts. X box-binding protein-1 (XBP1) splicing analysis showed no ER stress response. Altered gene expressions, including up-regulated MGST2 and HIF1A, and downregulated transforming growth factor beta-induced (TGFbi), were unveiled by cDNA microarray and validated by RT-qPCR. The TGFbi alteration occurred in transformants with wild type or mutated HBV. The altered MGST2 and HIF1A were found only with mutated HBV. The rtM204I/sW196* preS/S truncation may endorse the cell transformation and tumorigenesis ability via altered host gene expressions, including MGST2, HIF1A, and TGFbi. Downregulated TGFbi may be a common mechanism for oncogenicity in HBV surface truncation mutants.
Highlights
Hepatitis B virus (HBV) infection claims an enormous health burden on the globe, with over 250 million people living with chronic hepatitis B, and a significant proportion of them suffering from the consequences of cirrhosis and hepatocellular carcinoma
Transactivation activity occurred only when the premature stop codons were located within a region of the S gene, named the transactivity-on-region [16]. We investigated four such mutants in our 3TC-experienced hepatocellular carcinoma (HCC) cases for their nearby locations to the transactivity-on-region, and proved sL15*, sL21*, and sW172* mutants to be oncogenic [14,17]. rtM204I is a common 3TC-resistant mutation emerging in antiviral therapy, and may result in truncation or missense mutations on the overlapping surface gene
We focused on a few candidate genes using RT-qPCR, and confirmed a significant up-regulated MGST2, HIF1A, and downregulated transforming growth factor beta-induced (TGFbi) in YIDDst-cells
Summary
Hepatitis B virus (HBV) infection claims an enormous health burden on the globe, with over 250 million people living with chronic hepatitis B, and a significant proportion of them suffering from the consequences of cirrhosis and hepatocellular carcinoma. Since the approval of Lamivudine (3TC) as the first nucleoside analog (NA) in 1998 for the treatment of chronic hepatitis B virus (HBV) infection, this drug has been widely used around the world. The HBeAg seroconversion rate was enhanced from 17% to 50% after 2–5 years of extended use, but the treatment takes a toll, increasing drug-resistant mutants from 23 to 70% [2,3,4,5]. The benefit of NAs to reduce the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients is well documented [6,7,8,9]. The advantage may be offset if NA-resistant mutants emerge [6,10,11,12]
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