Anti-oncogene PTPN13 inactivation by hepatitis B virus X protein counteracts IGF2BP1 to promote hepatocellular carcinoma progression

Yongcong Yan,Jie Wang,Ruibin Chen,Qinghua Liu,Qianlei Zhou,Jianhong Lin,Jianlong Zhang,Zhenyu Zhou,Qiaodong Xu,Bing Ou,Mengyu Zhang,Chuanchao He,Haohan Liu,Qiming Zhou,Kai Mao,Zhiyu Xiao,Pinbo Huang

doi:10.1038/s41388-020-01498-3

Abstract

Hepatitis B x protein (HBx) affects cellular protein expression and participates in the tumorigenesis and progression of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Metabolic reprogramming contributed to the HCC development, but its role in HBV-related HCC remains largely unclear. Tyrosine-protein phosphatase nonreceptor type 13 (PTPN13) is a significant regulator in tumor development, however, its specific role in hepatocarcinogenesis remains to be explored. Here, we found that 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 in vitro and in vivo. 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 to −313 bp) in an epigenetically controlled manner associated with elevated DNA methylation and then inhibited PTPN13 transcription. In addition, 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 functional IGF2BP1. Overexpressing PTPN13 promoted c-Myc mRNA degradation independent of the protein tyrosine phosphatase (PTP) activity of PTPN13. 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 clinical HCC tissue samples. In summary, our findings demonstrate that 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.

Highlights

Liver cancer is the seventh most commonly diagnosed cancer (841,080 new cases annually) and the third leading cause of cancer death (781,631 cancer deaths) worldwideAnti-oncogene protein phosphatase nonreceptor type 13 (PTPN13) inactivation by hepatitis B virus X protein counteracts insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) to promote. . .according to the 2018 global cancer statistics [1], and Chinese patients account for nearly half of all patients and deaths [2]
PTPN13 expression was significantly lower in HBVpositive hepatocellular carcinoma (HCC) tissues (HBV + HCC) than in HBVnegative HCC tissues (HBV−HCC) (Fig. 1A, B and Fig. S1A)
Survival analysis revealed that the patients with low PTPN13 expression and an Hepatitis B virus (HBV)-positive history had the poorest overall survival (OS) among all patients analyzed (Fig. 1D)

Summary

Introduction

Liver cancer is the seventh most commonly diagnosed cancer (841,080 new cases annually) and the third leading cause of cancer death (781,631 cancer deaths) worldwideAnti-oncogene PTPN13 inactivation by hepatitis B virus X protein counteracts IGF2BP1 to promote. . .according to the 2018 global cancer statistics [1], and Chinese patients account for nearly half of all patients and deaths [2]. Liver cancer is the seventh most commonly diagnosed cancer (841,080 new cases annually) and the third leading cause of cancer death (781,631 cancer deaths) worldwide. 75–85% of all primary liver cancers are hepatocellular carcinoma (HCC). HBV factors, including the hepatitis B x protein (HBx), the pre-S2/S gene and the HBV-spliced protein, have been implicated in liver cancer progression [5]. HBx, a well-known oncogenic protein in HBVrelated hepatocarcinogenesis, modulates the expression of important genes and affects the cytoplasmic modulation of signal transduction pathways [6, 7]. Metabolic reprogramming is a selective advantage that supports cancer cell biosynthetic needs, rapid proliferation and tumor growth [8]. Uncovering the metabolic alterations and mechanisms underlying HBx-mediated tumorigenesis is urgently needed

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Conclusion