Hepatocellular carcinoma is the most frequent cancer worldwide, responsible for approximately 1,000,000 deaths annually, most of them in the Far East and in sub-Saharan Africa. It usually presents at an advanced stage and has a poor prognosis. There is evidence of an etiologic role for hepatitis B virus infection in the etiology of hepatocellular carcinoma. Carriers of the virus are 94 times more at risk for hepatocellular carcinoma than noncarriers. In many cases hepatitis B virus DNA is integrated within the cellular genome of the tumor. Programs have been established to detect hepatocellular carcinoma at an early stage; persons at high risk are regularly screened by measurement of serum alpha-fetoprotein levels and ultrasound examination of the liver. Surgical resection offers the only hope of cure at present, as chemotherapy, radiotherapy, and immunotherapy have not shown promise. Ideally, surgery should be done on small asymptomatic tumors.
Hepatitis C virus (HCV) is a serious global health problem and establishes chronic infection in a significant number of infected humans worldwide. Interferon (IFN) and IFN-stimulated genes (ISGs) are amplified during HCV infection but fail to eliminate virus from the liver in a large number of infected patients, and the mechanism is not fully understood. MicroRNAs (miRNAs) have been implicated in the control of many biological processes, including IFN signaling. To gain more insights into the role of cellular miRNAs in possible countermeasures of HCV for suppression of the host antiviral response, a miRNA array was performed by using primary human hepatocytes infected with in vitro cell culture-grown HCV. A group of miRNAs were modulated in HCV-infected primary human hepatocytes. We focused on miR-373, as this miRNA was significantly upregulated in HCV-infected primary human hepatocytes. Here, we analyzed the function of miR-373 in the context of HCV infection. HCV infection upregulates miR-373 expression in hepatocytes and HCV-infected liver biopsy specimens. Furthermore, we discovered that miR-373 directly targets Janus kinase 1 (JAK1) and IFN-regulating factor 9 (IRF9), important factors in the IFN signaling pathway. The upregulation of miR-373 by HCV also inhibited STAT1 phosphorylation, which is involved in ISG factor 3 (ISGF3) complex formation and ISG expression. The knockdown of miR-373 in hepatocytes enhanced JAK1 and IRF9 expression and reduced HCV RNA replication. Taken together, our results demonstrated that miR-373 is upregulated during HCV infection and negatively regulated the type I IFN signaling pathway by suppressing JAK1 and IRF9. Our results offer a potential therapeutic approach for antiviral intervention.
H epatitis C virus is a member of the Hepacivirus genus of theFlaviviridae family and is represented by seven major genotypes. The virion contains a 9.6-kb single-stranded RNA genome of positive polarity, with highly invariant 5= and 3= untranslated regions (UTRs) flanking a long open reading frame (ORF) that is translated via an internal ribosome entry site (IRES) (1). The resulting polyprotein is processed by viral and cellular proteases to yield structural (core, E1, and E2/p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) proteins.HCV infection is one of the main causes of chronic liver disease. It is estimated that ϳ200 million people are chronically infected with HCV worldwide (2, 3). Chronic HCV infection is linked to a deregulation of innate and adaptive immune signaling mechanisms (4). Despite progress in understanding immunity against HCV infection and its pathogenesis along with the development of highly effective direct-acting antivirals (DAAs), a prophylactic anti-HCV vaccine is still lacking, and at least 2 million new HCV infections occur each year (5).MicroRNAs (miRNAs) are a class of ϳ18-to 22-nucleotidelong noncoding RNA molecules that function through posttranscriptional regulation of gene expression. The production of miRNAs requires several processi...
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