Oncogenic transcriptomic profile is sustained in the liver after the eradication of the hepatitis C virus

Abstract

Hepatocellular carcinoma (HCC) developing after hepatitis C virus (HCV) eradication is a serious clinical concern. However, molecular basis for the hepatocarcinogenesis after sustained virologic response (SVR) remains unclear. In this study, we aimed to unveil the transcriptomic profile of post-SVR liver tissues and explore the molecules associated with post-SVR carcinogenesis. We analysed 90 RNA-sequencing datasets, consisting of noncancerous liver tissues including 20 post-SVR, 40 HCV-positive and 7 normal livers, along with Huh7 cell line specimens before and after HCV infection and eradication. Comparative analysis demonstrated that cell cycle- and mitochondrial function-associated pathways were altered only in HCV-positive noncancerous liver tissues, while some cancer-related pathways were upregulated in the noncancerous liver tissues of both post-SVR and HCV-positive cases. The persistent upregulation of carcinogenesis-associated gene clusters after viral clearance was reconfirmed through in vitro experiments, of which, CYR61, associated with liver fibrosis and carcinogenesis in several cancer types, was the top enriched gene and co-expressed with cell proliferation-associated gene modules. To evaluate whether this molecule could be a predictor of hepatocarcinogenesis after cure of HCV infection, we also examined 127 sera from independent HCV-positive cohorts treated with direct-acting antivirals, including 60 post-SVR-HCC patients, and found that the elevated serum Cyr61 was significantly associated with early carcinogenesis after receiving direct-acting antiviral therapy. In conclusion, some oncogenic transcriptomic profiles are sustained in liver tissues after HCV eradication, which might be a molecular basis for the liver cancer development even after viral clearance. Among them, upregulated CYR61 could be a possible biomarker for post-SVR HCC.

Hepatocellular carcinoma after treatment of hepatitis C with direct-acting antivirals: a critical re-appraisal

“…Other factors not restored in liver tissue after DAAs treatment that may contribute to HCC are the decrease of microRNA-122 and the upregulation of oncogenic transcriptomic profiles like CYR61 [113][114][115] . Moreover, a reduction of mucosal-associated invariant T cell cytotoxicity, possibly caused by rapid phenotyping changes of these cells after DAAs treatment, attenuates their action against cancer cells.…”

The role of ceRNA-mediated diagnosis and therapy in hepatocellular carcinoma

“…Other risk factors include chemical carcinogens exposure, obesity, diabetes, and alcohol abuse (Fig. 1C) [10][11][12][13], and the HCC incidence has been on the rise in recent years. Meanwhile, there are significant geographical differences in the risk factors for HCC, mirroring the variation in global distribution patterns.…”

Molecular Crosstalk between the Hepatitis C Virus and the Extracellular Matrix in Liver Fibrogenesis and Early Carcinogenesis

“…Notably, CCN2 is also known as the connective tissue growth factor (CTGF) [ 166 ]. Increased serum levels of CYR61 or CCN1 were proposed as biomarkers of HCV-induced HCC post-SVR [ 14 ] (see Section 1 ). The link between HCV pathogenesis and thrombospondin-1 has already been described in Section 3.2.2 .1.…”

“…For example, a variant in the core protein of HCV genotype 1b is associated with increased HCC incidence post SVR [ 13 ]. A more recent study pointed at sustained oncogenic transcriptomic profiles in liver tissues after HCV eradication with DAAs [ 14 ]. Among them, increased serum levels of CYR61 could be a possible biomarker of HCC post-SVR [ 14 ] (see Section 3.2.4 ).…”

“…A more recent study pointed at sustained oncogenic transcriptomic profiles in liver tissues after HCV eradication with DAAs [ 14 ]. Among them, increased serum levels of CYR61 could be a possible biomarker of HCC post-SVR [ 14 ] (see Section 3.2.4 ). Thus, SVR is a virological cure but is not necessarily translated into a cure from risks of liver disease, particularly for patients with cirrhotic-stage fibrosis.…”