Downregulation of SHIP2 by Hepatitis B Virus X Promotes the Metastasis and Chemoresistance of Hepatocellular Carcinoma through SKP2

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.

Anti-cancer therapeutic benefit of red guava extracts as a potential therapy in combination with doxorubicin or targeted therapy for triple-negative breast cancer cells

“…Red guavas were kindly provided by a farmer, Lin Chao Hsiung (A Fong guava farm, Houbi Dist., Tainan City 731, Taiwan). Doxorubicin, Erlotinib (Tarceva; Roche, Basel, Germany) and Gefitinib (Iressa; Astra Zeneca, London, England) were dissolved in dimethyl sulfoxide (DMSO) and the concentrations of drugs were referred to previous studies [15,25,30]…”

Hepatitis B core antigen modulates exosomal miR-135a to target vesicle-associated membrane protein 2 promoting chemoresistance in hepatocellular carcinoma

“…Our research group and other groups have published several articles on HBx protein promoted chemotherapeutic resistance in HCC[ 65 - 67 ]. A recently published paper concludes that HBx protein leads to resistance to the chemotherapy drug 5-Fluorouracil in HCC by downregulating SHIP2 through SKP2[ 65 ].…”

“…Our research group and other groups have published several articles on HBx protein promoted chemotherapeutic resistance in HCC[ 65 - 67 ]. A recently published paper concludes that HBx protein leads to resistance to the chemotherapy drug 5-Fluorouracil in HCC by downregulating SHIP2 through SKP2[ 65 ]. We also reported that HBx protein can promote Dox chemoresistance in HCC through overexpression of Variant 1 of KIAA0101[ 66 ] and Transcript variant 2 of the chemokine-like factor (CKLF1)[ 67 ].…”

The Functions of Hepatitis B Virus Encoding Proteins: Viral Persistence and Liver Pathogenesis

“…It is shown in vitro experiments that HBx induces Skp2 expression and thereby down-regulates SHIP2 by inducing a notable accumulation of polyubiquitinated SHIP2 in HCC cells. The down-regulation of SHIP2 leads to HCC cell migration, elevated glucose uptake and drug resistance to 5-Fluorouracil (5-FU) ( 89 ).…”