title: 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.
authors.affiliation: The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.|Department of Urology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200438, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: The Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Ming-da
authors.initials: MD
authors.lastname: Wang
authors.affiliation: Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200438, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Cheng
authors.affiliation: Changzheng Hospital, Second Military Medical University, Fengyang Road Shanghai 200003, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.affiliation: Data Scientist, Liberty Mutual Group, 157 Berkeley Street, Boston, MA 02116, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Dong
authors.affiliation: Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200438, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Zhang
authors.affiliation: The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Peng-Peng
authors.initials: PP
authors.lastname: Li
authors.affiliation: The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Lin
authors.affiliation: The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Ze-Ya
authors.initials: ZY
authors.lastname: Pan
authors.affiliation: The Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Meng-Chao
authors.initials: MC
authors.lastname: Wu
authors.affiliation: The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Zhou
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000235:genetics; D054377:Chemokine CXCL12 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006515:Hepatitis B virus / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D014411:Neoplastic Stem Cells / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D051176:beta Catenin; C057628:hepatitis B virus X protein; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2