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

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.

Identification of Therapeutic Targets for the Selective Killing of HBV-Positive Hepatocytes

“…ARRB1 has been indicated to promote HCC, and was upregulated by hepatitis B virus X protein (HBx) in mouse models [ 59 ]. Interestingly, among other candidate genes, some genes are related to the progression of HCC, including, GATAD1 [ 44 , 45 ], FOXK1 [ 46 ], RALGAPA2 [ 47 ], PDE4A [ 48 ], TRIP6 [ 49 ], SPTBN1 [ 53 ], PTP4A3 [ 54 ], TRIM4 [ 56 ], and LMNB1 [ 60 ]. These results suggest that the 36 candidate genes are associated with the functions of HBV and hepatocytes; however, this association needs to be further validated.…”

Dual Role of the PTPN13 Tyrosine Phosphatase in Cancer

“…Its methylation is consistently associated with decreased PTPN13 expression [103], and has been observed in many hematologic (94% of 16 non-Hodgkin lymphoma cell lines, 50% of 6 Hodgkin lymphoma cell lines) and solid cancer cell lines (67% of 12 HCC cell lines, 60% of 10 gastric cancer cell lines, and 30% of 10 breast cancer cell lines). Similarly, Yeh et al reported that the PTPN13 promoter is methylated in 66% of 12 HCC samples without loss of heterozygosity (LOH) of chromosome 4q [104]. Moreover, Wang et al found that the PTPN13 promoter is methylated in 60% of 47 diffuse large B cell lymphoma samples, compared with 6.3% of 16 non-tumor tissue samples [112].…”

“…More recently, Yan Y. et al demonstrated that, in HCC, the hepatitis B virus X protein regulates PTPN13 expression via the DNA methyltransferase 3A, which binds to the PTPN13 promoter and induces the hypermethylation of its CpG islands. This loss of PTPN13 leads to an increase in c-Myc levels and signaling through the loss of its competitive interaction with IGFP2B1 that protects c-Myc mRNA from degradation [104].…”

“…67% of 12 HCC cell lines, 60% of 10 gastric ll lines, and 30% of 10 breast cancer cell lines). Similarly, Yeh et al reported that the PTPN13 r is methylated in 66% of 12 HCC samples without loss of heterozygosity (LOH) of ome 4q[104]. Moreover, Wang et al found that the PTPN13 promoter is methylated in 60% fuse large B cell lymphoma samples, compared with 6.3% of 16 non-tumor tissue samples ecent study[62] established four esophageal and Barrett's esophagus adenocarcinoma based on their genome methylation rate.…”

MicroRNA Dysregulation in Epilepsy: From Pathogenetic Involvement to Diagnostic Biomarker and Therapeutic Agent Development

“…Silencing miR-132 inhibited the aberrant formation of dendritic spines and chronic spontaneous seizures in a lithiumpilocarpine-induced epileptic mouse model (Yuan et al, 2016). Experiments with cultured epileptic neurons suggesting that miR-132 silencing exerted a neuroprotective effect through the miR-132/p250GAP/Cdc42 pathway (Yuan et al, 2016). miR-204 directly targets and downregulates TrkB protein in various diseases (Xiang et al, 2016).…”