1013P PTPN13 inactivation by hepatitis B virus X regulates metabolic reprogramming for hepatocellular carcinoma progression

Abstract

Hepatitis B x protein (HBx) participates in the tumorigenesis and progression of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). PTPN13 is a significant regulator in tumor development, however, its specific role in hepatocarcinogenesis remains to be explored. We herein explore the function and mechanism of PTPN13-triggered metabolic reprogramming in HBV related hepatocarcinogenesis. QRT-PCR, Western blotting, and immunohistochemistry were used to analyze HCC cell lines, and human and mouse HCC tumor tissues, and to correlate PTPN13 expression with patient prognosis. The underlying regulatory mechanisms were studied with both ex vivo analyses and vitro experiments, such as immunoprecipitation, Chromatin immunoprecipitation and Electrophoretic mobility shift assay, mammalian two-hybrid system and RNA-binding protein immunoprecipitation. Decreased PTPN13 expression was associated with HBV/HBx. Patients with low PTPN13 expression showed a poor prognosis. Functional assays revealed that PTPN13 inhibited proliferation and tumorigenesis. Further mechanistic studies indicated that HBx inhibited PTPN13 expression by upregulating the expression of DNMT3A and interacting with DNMT3A. Furthermore, we found that DNMT3A bound to the PTPN13 promoter (-343∼-313 bp) in an epigenetically controlled manner associated with elevated DNA methylation and then inhibited PTPN13 transcription. Additionally, we identified IGF2BP1 as a novel PTPN13-interacting gene and demonstrated that PTPN13 influences c-Myc expression by directly and competitively binding to IGF2BP1 to decrease the intracellular concentration of IGF2BP1. Importantly, we discovered that the PTPN13-IGF2BP1-c-Myc axis was important for cancer cell growth through promoting metabolic reprogramming. We verified the significant negative correlations between PTPN13 expression and c-Myc, PSPH, and SLC7A1 expression in HCC tissues. PTPN13 is a novel regulator of HBV-related hepatocarcinogenesis and may play an important role in HCC. PTPN13 may serve as a prognostic marker and therapeutic target in HBV-related HCC patients.