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Hepatitis B virus X protein promotes the stem-like properties of OV6⁺ cancer cells in hepatocellular carcinoma.

ABSTRACT: Hepatitis B virus X protein (HBx) and cancer stem-like cells (CSCs) have both been implicated in the occurrence and development of HBV-related hepatocellular carcinoma (HCC). However, whether HBx contributes to the stem-like properties of OV6⁺ CSCs in HCC remains elusive. In this study, we showed that the concomitant expression of HBx and OV6 was closely associated with the clinical outcomes and prognosis of patients with HBV-related HCC. HBx was required for the stem-like properties of OV6⁺ liver CSCs, including self-renewal, stem cell-associated gene expression, tumorigenicity and chemoresistance. Mechanistically, HBx enhanced expression of MDM2 by directly binding with MDM2 and inhibiting its ubiquitin-directed self-degradation. MDM2 translocation into the nucleus was also upregulated by HBx and resulted in enhanced transcriptional activity and expression of CXCL12 and CXCR4 independent of p53. This change in expression activated the Wnt/?-catenin pathway and promoted the stem-like properties of OV6⁺ liver CSCs. Furthermore, we observed that the expression of any two indicators from the HBx/MDM2/CXCR4/OV6 axis in HCC biopsies could predict the prognosis of patients with HBV-related HCC. Taken together, our findings indicate the functional role of HBx in regulating the stem-like properties of OV6⁺ CSCs in HCC through the MDM2/CXCL12/CXCR4/?-catenin signaling axis, and identify HBx, MDM2, CXCR4 and OV6 as a novel prognostic pathway and potential therapeutic targets for patients with HBV-related HCC patients.

SUBMITTER: Wang C

PROVIDER: S-EPMC5386392 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Hepatitis B virus X protein promotes the stem-like properties of OV6<sup>+</sup> cancer cells in hepatocellular carcinoma.

Wang Chao C Wang Ming-da MD Cheng Peng P Huang Hai H Dong Wei W Zhang Wei-Wei WW Li Peng-Peng PP Lin Chuan C Pan Ze-Ya ZY Wu Meng-Chao MC Zhou Wei-Ping WP

Cell death & disease 20170119 1

Hepatitis B virus X protein (HBx) and cancer stem-like cells (CSCs) have both been implicated in the occurrence and development of HBV-related hepatocellular carcinoma (HCC). However, whether HBx contributes to the stem-like properties of OV6<sup>+</sup> CSCs in HCC remains elusive. In this study, we showed that the concomitant expression of HBx and OV6 was closely associated with the clinical outcomes and prognosis of patients with HBV-related HCC. HBx was required for the stem-like properties ...[more]

PMID: 28102846

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Project description:BackgroundmiR-500a-3p has been demonstrated to be involved in the development, progression and metastasis in several human cancers. Constitutive activation of JAK/STAT3 signaling pathway has been reported to play an important role in the development and progression of hepatocellular carcinoma (HCC).The purpose of this study was to determine the biological roles and clinical significance of miR-500a-3p in HCC and to identify whether miR-500a-3p has an effect on the activity of JAK/STAT3 signaling in HCC.MethodsmiR-500a-3p expression was examined by real-time PCR in 8 paired HCC tissues and individual 120 HCC tissues respectively. Statistical analysis was performed to explore the clinical correlation between miR-500a-3p expression and clinicopathological features and overall and relapse-free survival in HCC patients. In vitro and in vivo assays were performed to investigate the biological roles of miR-500a-3p in HCC. The bioinformatics analysis, real-time PCR, western blot and luciferase reporter assay were performed to discern and examine the relationship between miR-500a-3p and its potential targets. Clinical correlation of miR-500a-3p with its targets was examined in HCC tissues.ResultsmiR-500a-3p is dramatically elevated in HCC tissues and cells and high expression of miR-500a-3p correlates with poor overall and relapse-free survival in HCC patients. Upregulating miR-500a-3p enhances, while silencing miR-500a-3p suppresses, the spheroid formation ability, fraction of side population and expression of cancer stem cell factors in vitro and tumorigenicity in vivo in HCC cells. Our findings further reveal miR-500a-3p promotes the cancer stem cell characteristics via targeting multiple negative regulators of JAK/STAT3 signaling pathway, including SOCS2, SOCS4 and PTPN11, leading to constitutive activation of STAT3 signaling. Moreover, the inhibitory effects of anti-miR-500a-3p on cancer stem cell phenotypes and activity of STAT3 signaling were reversed by silencing SOCS2, SOCS4 and PTPN11 in miR-500a-3p-downexpressing cells, respectively. Clinical correlation of miR-500a-3p with the targets was examined in human HCC tissues.Conclusionour results uncover a novel mechanism by which miR-500a-3p promotes the stemness maintenance of cancer stem cell in HCC, suggesting that silencing miR-500a-3p may serve as a new therapeutic strategy in the treatment of hepatocellular carcinoma.

Dataset Information

Hepatitis B virus X protein promotes the stem-like properties of OV6⁺ cancer cells in hepatocellular carcinoma.

Publications

Hepatitis B virus X protein promotes the stem-like properties of OV6<sup>+</sup> cancer cells in hepatocellular carcinoma.

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Hepatitis B virus X protein promotes the stem-like properties of OV6+ cancer cells in hepatocellular carcinoma.

Publications

Hepatitis B virus X protein promotes the stem-like properties of OV6<sup>+</sup> cancer cells in hepatocellular carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Hepatitis B virus X protein promotes the stem-like properties of OV6⁺ cancer cells in hepatocellular carcinoma.