Abstract
Infection of hepatitis C virus (HCV) is associated with primary hepatocellular carcinoma (HCC). However, its underlying molecular mechanisms remain enigmatic. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2), a new negative regulator of immunity, plays significant roles in modulating inflammation and tumorigenesis. We hypothesized that TIPE2 might be involved in the development of HCV-induced HCC. To test this hypothesis, the expression of TIPE2 was determined by Western blot in the tumor and pericarcinomatous tissues collected from ten HCV-positive HCC patients; the interaction between TIPE2 and HCV-encoded non-structural proteins was analyzed by immunoprecipitation and immunofluorescence assays, and tumorigenesis and its mechanisms were studied in cell models and nude mice. Our results demonstrated that the expression of TIPE2 was significantly reduced in HCC tissues compared to that in the paracarcinoma tissues. HCV-encoded non-structural protein NS5A could specifically interact with TIPE2 and induce its degradation. Downregulation of TIPE2 by shRNA in cell lines increased genomic DNA damage and promoted cell colony formation in vitro and tumorigenesis in nude mice. In contrast, overexpression of TIPE2 had an opposite effect. Downregulation of TIPE2 by NS5A is associated with genomic DNA instability and HCV-induced HCC development. Thus, TIPE2 may be a new therapeutic target for the treatment of HCV-associated HCC.
Highlights
There are more than 150 million hepatitis C virus (HCV)-infected individuals in the world [1]
Lower level of Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) was observed in the hepatoma cell lines such as Huh7 and HepG2 cells compared to non-cancer Changliver cells
These results suggested that TIPE2 is involved in HCV-associated hepatocellular carcinoma (HCC)
Summary
There are more than 150 million hepatitis C virus (HCV)-infected individuals in the world [1]. Chronic HCV infection is highly associated with hepatocellular carcinoma (HCC). Among the ten HCV encoded structural (core, E1, E2) and non-structural (P7, NS2, NS3, NS4A, NS4B, NS5A, NS5B) proteins [4], core, NS3, NS4B, and NS5A have been shown to directly activate oncogenic molecular pathways and promote tumor formation in vivo [5,6,7,8]. The strategies employed by HCV and encoded proteins to induce tumor formation include chronic inflammation, reactive oxidative stress (ROS), steatosis, fibrosis, and so on. DNA damage/repair is associated with almost all of the above pathogenic patterns. In HCC patients, accumulation of DNA damage has been detected in the peripheral blood lymphocytes [14] and abundant H2AX+ T lymphocytes were found in the liver [15]
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