Regulation of ERK and AKT Pathways by Hepatitis B Virus X Protein via Notch1 Pathway in Hepatocellular Carcinoma

Liao, Bo; Zhou, Honghao; Liang, Huifang; Li, Changhai

doi:10.20944/preprints201609.0074.v1

Cited by 9 publications

(10 citation statements)

References 30 publications

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“…HBx-enhanced androgen receptor activity is suppressed by sorafenib via the activation of SHP-1 phosphatase, which antagonizes Akt/GSK3β and c-Src pathway activation via HBx [13]. HBx activates the Notch1 pathway, which inhibits dual-specificity phosphatase 1 (DUSP1) and PTEN expression, promoting HCC cell survival [14].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…HBx, the main regulatory protein encoded by HBV, is not considered to be directly transforming but plays a significant positive role in HBVassociated hepatocarcinogenesis (10). HBx has been reported to support β-catenin activation, which is highly associated with HBV-positive HCC (26,36,37). However, transgenic mice expressing HBx in hepatocytes under control of the α-1-antitrypsin promoter (ATX mice) do not develop tumors at higher rates than wild-type controls (21), and we did not observe significant β-catenin activation in 12-month-old ATX mice without other intervention.…”

Section: Discussionmentioning

confidence: 99%

Constitutive Androstane Receptor and Hepatitis B Virus X Protein Cooperatively Induce β-catenin-Activated Liver Tumors

Scott

Liu

Klatt

et al. 2020

Preprint

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Background and Aims: The xenobiotic nuclear receptor Constitutive Androstane Receptor (CAR) is essential for xenobiotic tumor promotion in mouse models. In these models, β-catenin is genetically activated in approximately 80% of tumors. Chronic Hepatitis B Virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), and β-catenin activation is also frequently activated in HBV-associated HCCs. The goal of this research was to determine whether activation of CAR in a mouse model of chronic HBV infection would result in tumor formation and whether these tumors would display increased β-catenin activation. Approach and Results: We treated transgenic mice expressing the HBV X protein (HBx) in hepatocytes with a single dose of the potent CAR agonist TCPOBOP. After 10 months, these mice developed large liver tumors that are characterized by β-catenin nuclear localization and upregulation of β-catenin targets. The β-catenin regulator FoxM1 and the oxidative stress master regulator Nrf2, both of which are CAR gene targets, were also overactivated in tumors. The CAR/HBx tumors share a conserved gene signature with HBV-related human hepatocellular carcinoma. Conclusions: Activation of CAR in the presence of HBx results in tumors with strong β-catenin activation. The mouse model we have described reflects the gene expression patterns seen in human HBV-associated HCC and presents an attractive basis for future studies.

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“…Activation of AKT by HBx protein downregulates HNF4α transcription in rat hepatocyte and suggested to contribute to the development of HBV-associated HCC [14,32]. In addition to AKT signaling pathway, HBx can regulate ERK through Notch1 pathway in HCC [14,20].…”

Section: Discussionmentioning

confidence: 99%

“…Previous reports have shown that the rat sarcoma virus (Ras)/Raf/MEK/ERK signaling pathway, c-Jun N-terminal kinase (JNK) pathway and phosphoinositide 3-kinase (PI3K)/AKT signaling pathway are the major signaling pathways regulating cell proliferation and differentiation in HCC cells [17,18]. Among these, ERK signaling pathway is one of the main pathways in HCC which is associated with cell proliferation [19], and previous studies have revealed that HBx activates ERK signaling pathway [20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Suppression of Hepatocyte Nuclear Factor 4 Alpha by Long-Term Infection of Hepatitis B Virus Contributes to Tumor Cell Proliferation

Park¹,

Ha²,

Dezhbord³

et al. 2020

Preprint

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Hepatitis B virus (HBV) infection is a major factor in development of various liver diseases such as hepatocellular carcinoma (HCC). Among HBV encoded proteins, HBV X protein (HBx) is known to play key role in development of HCC. Hepatocyte nuclear factor 4α (HNF4α) is a nuclear transcription factor which is critical for hepatocyte differentiation. However, the expression level as well as its regulatory mechanism in HBV infection have yet to be clarified. Here, we observed the suppression of HNF4α in cells which stably express HBV whole genome or HBx protein alone, while transient transfection of HBV replicon or HBx plasmid had no effect on the HNF4α level. Importantly, in the stable HBV- or HBx-expressing hepatocytes, the downregulated level of HNF4α was restored by inhibiting ERK signaling pathway. Our data showed that HNF4α was suppressed during long-term HBV infection in cultured HepG2-NTCP cells as well as in mouse model following hydrodynamic injection of pAAV-HBV or in mice intravenously infected with rAAV-HBV. Importantly, HNF4α downregulation increased cell proliferation which contributed to the formation and development of tumor in xenograft nude mice. The data presented here provided several proofs for the effect of HBV infection in manipulating HNF4α regulatory pathway in HCC development.

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Regulation of ERK and AKT Pathways by Hepatitis B Virus X Protein via Notch1 Pathway in Hepatocellular Carcinoma

Cited by 9 publications

References 30 publications

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

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

Constitutive Androstane Receptor and Hepatitis B Virus X Protein Cooperatively Induce β-catenin-Activated Liver Tumors

Suppression of Hepatocyte Nuclear Factor 4 Alpha by Long-Term Infection of Hepatitis B Virus Contributes to Tumor Cell Proliferation

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