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/β-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/β-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.

Reciprocal Network between Cancer Stem-Like Cells and Macrophages Facilitates the Progression and Androgen Deprivation Therapy Resistance of Prostate Cancer

“…By IHC, the positive staining for OV6 in normal prostate basal cells suggests that OV6 is an epithelial marker ( Fig. 1A), which is consistent with the results of our previous studies (24)(25)(26)(27). Samples from locally advanced prostate cancer (LAPC), CRPC, and neuroendocrine prostate cancer (NEPC) exhibited higher OV6 expression than localized prostate cancers (Fig.…”

“…In this study, we demonstrated that a subpopulation in prostate cancer harboring CSC characteristics could be identified by the epithelial marker OV6, which serves as a CSC marker in epithelium-derived malignant tumors and was associated with patient prognosis in our previous studies (24)(25)(26)(27). We demonstrated that an intracellular pathway, autophagy-related gene 7 (ATG7)/ b-catenin/OCT4, sustained the self-renewal of OV6 þ cells and facilitated the progression and ADT resistance of prostate cancer.…”

A Coiled‐Coil Domain Containing 50 Splice Variant Is Modulated by Serine/Arginine‐Rich Splicing Factor 3 and Promotes Hepatocellular Carcinoma in Mice by the Ras Signaling Pathway

“…On the other hand, HBx exhibited functions through alteration of cellular localization of proteins involved in cell growth. For example, HBx bound to murine double minute 2 (MDM2) and promoted its translocation into the nucleus, resulting in enhanced transcriptional activity of MDM2 . Our data demonstrated that HBx enhanced 14‐3‐3β–mediated cytoplasmic retaining of SRSF3.…”

BNIP3L-Dependent Mitophagy Promotes HBx-Induced Cancer Stemness of Hepatocellular Carcinoma Cells via Glycolysis Metabolism Reprogramming

“…The link between HBx-expressing and CSCs in HBV-related HCC has gradually become a research hotspots. It has been reported that HBx promoted a CD44 + CD133 + CSCs subset in malignant transformed L-02 cells and Huh7 cells, and HBx regulated tumorigenicity, self-renewal, and drug resistance in HCC cells [4,35,36]. In the present study, we selected two different HCC cells with distinct proportion of ABCG2 + subset, which Huh7 cells had a low ABCG2 + subset ratio and MHCC-97H had a high ABCG2+ subset ratio.…”