Molecular Mechanisms of Hepatocarcinogenesis Following Sustained Virological Response in Patients with Chronic Hepatitis C Virus Infection

Abstract

Despite the success of direct-acting antiviral (DAA) agents in treating chronic hepatitis C virus (HCV) infection, the number of cases of HCV-related hepatocellular carcinoma (HCC) is expected to increase over the next five years. HCC develops over the span of decades and is closely associated with fibrosis stage. HCV both directly and indirectly establishes a pro-inflammatory environment favorable for viral replication. Repeated cycles of cell death and regeneration lead to genomic instability and loss of cell cycle control. DAA therapy offers >90% sustained virological response (SVR) rates with fewer side effects and restrictions than interferon. While elimination of HCV helps to restore liver function and reverse mild fibrosis, post-SVR patients remain at elevated risk of HCC. A series of studies reporting higher than expected rates of HCC development among DAA-treated patients ignited debate over whether use of DAAs elevates HCC risk compared to interferon. However, recent prospective and retrospective studies based on larger patient cohorts have found no significant difference in risk between DAA and interferon therapy once other factors are taken into account. Although many mechanisms and pathways involved in hepatocarcinogenesis have been elucidated, our understanding of drivers specific to post-SVR hepatocarcinogenesis is still limited, and lack of suitable in vivo and in vitro experimental systems has hampered efforts to examine etiology-specific mechanisms that might serve to answer this question more thoroughly. Further research is needed to identify risk factors and biomarkers for post-SVR HCC and to develop targeted therapies based on more complete understanding of the molecules and pathways implicated in hepatocarcinogenesis.

Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip

“…Tumor suppressor genes silenced by core include secreted frizzled-related protein (SFRP) [126], which promotes epithelial-mesenchymal transition (EMT) and deregulates Wnt/ß-catenin signaling as major pathways involved in HCC development [128]. HCV-induced hypermethylation of cancer-related genes such as APC, p73, p14, and O 6 MGMT (summarized in [129]) and perturbed methylation in repetitive DNA elements have been observed [130], suggesting a relevance for HCV-related HCC.…”

Risk of Hepatocellular Carcinoma after HCV Clearance by Direct-Acting Antivirals Treatment Predictive Factors and Role of Epigenetics

“…In many studies, an early appearance of HCC was detected as early as six–nine months after discontinuation of DAAs therapy [ 29 , 30 , 31 , 33 , 34 , 35 , 36 , 37 ]. To explain this event, two prevailing hypotheses have been made: the presence of small HCC nodules already before the start of treatment or the induction of carcinogenesis by the DAAs mediated by largely unknown immunological mechanisms [ 68 , 69 , 70 ]. In the first case, small nodules may have escaped the ultrasound screening for pre-treatment with DAAs, whereas contrast enhancement examinations (MRI or CT) are reserved for cases in which basic nodules have already been identified [ 71 ].…”

Hepatitis C Virus Translation Regulation

“…However, most HCV infections remain inapparent [5,6], and the virus infection can become chronic in about 60% to 70 % of all infections [7], often without being noticed. Chronic infection can, in the long run, result in liver cirrhosis and liver cancer (hepatocellular carcinoma, HCC) [8][9][10], while a metabolic reprogramming of the infected cells according to the "Warburg effect" like in cancer cells can be observed only a few days after the onset of HCV replication [11]. Moreover, inapparent replication of the virus usually results in unnoticed spread of the virus to other individuals, a fact that is a major challenge for surveillance, health care, and treatment [12].…”