Abstract
Hepatitis B virus (HBV)-encoded X protein (HBx) plays an important role in the development of hepatocellular carcinoma (HCC). The protein SH2 domain containing inositol 5-phosphatase 2 (SHIP2) belongs to the family of enzymes that dephosphorylate the 5 position of PI(3,4,5)P3 to produce PI(3,4)P2. Expression of SHIP2 has been associated with several cancers including HCC. However, its role in the development of HBV-related HCC remains elusive. In this study, we performed tissue microarray analysis using 49 cases of HCC to explore SHIP2 expression changes and found that SHIP2 was downregulated in HBV-positive HCC. In addition, S-phase kinase-associated protein 2 (SKP2), a component of the E3 ubiquitin–ligase complex, was increased in HCC cell lines that overexpressed HBx, which also showed a notable accumulation of polyubiquitinated SHIP2. Moreover, HCC cells with silenced SHIP2 had increased expression of mesenchymal markers, which promotes cell migration, enhances glucose uptake, and leads to resistance to the chemotherapy drug (5-Fluorouracil, 5-FU). Taken together, our results demonstrate that HBx downregulates SHIP2 through SKP2 and suggest a potential role for SHIP2 in HBx-mediated HCC migration.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies and is a leading cause of cancer-related deaths in the world
We demonstrated that S-phase kinase-associated protein 2 (SKP2) is able to directly regulate SH2 domain containing inositol 5-phosphatase 2 (SHIP2) in the promotion of hepatocellular carcinoma (HCC) migration mediated by HBV x protein (HBx)
Our results suggest that HBx mediates migration and invasion of HCC cells by SHIP2 downregulation and stimulation of its degradation by the E3 ligase SKP2
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies and is a leading cause of cancer-related deaths in the world. The frequency of hepatitis B surface antigen in the general population ranges from 2% to 20%, indicating chronic infection with hepatitis B virus (HBV), which leads to the development of HCC [1,2]. HBV x protein (HBx), which is encoded by the smallest open reading frame of the HBV genome, is associated with hepatocellular carcinogenesis [3,4]. HBx is a multifunctional viral regulator that modulates protein degradation via interacting with proteasome subunits [5,6]. The ubiquitin–proteasome system has an important role in the regulation of diverse cellular processes, including cell cycle control, transcription, apoptosis, cell adhesion, and tumor growth, through targeted degradation of regulatory proteins [7,8].
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