Wang Chao, Wang Ming-da, Cheng Peng, Huang Hai, Dong Wei, Zhang Wei-Wei, Li Peng-Peng, Lin Chuan, Pan Ze-Ya, Wu Meng-Chao, Zhou Wei-Ping
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.
Cell Death Dis. 2017 Jan 19;8(1):e2560. doi: 10.1038/cddis.2016.493.
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.
乙型肝炎病毒X蛋白（HBx）和癌症干细胞（CSCs）均与乙型肝炎病毒相关肝细胞癌（HCC）的发生和发展有关。然而，HBx是否促成了HCC中OV6癌症干细胞的干细胞样特性仍不清楚。在本研究中，我们表明HBx和OV6的共表达与乙型肝炎病毒相关HCC患者的临床结局和预后密切相关。HBx是OV6肝脏癌症干细胞的干细胞样特性所必需的，包括自我更新、干细胞相关基因表达、致瘤性和化疗耐药性。机制上，HBx通过直接与MDM2结合并抑制其泛素介导的自我降解来增强MDM2的表达。HBx还上调了MDM2向细胞核的转位，并导致CXCL12和CXCR4的转录活性和表达增强，且不依赖于p53。这种表达变化激活了Wnt/β-连环蛋白通路，并促进了OV6肝脏癌症干细胞的干细胞样特性。此外，我们观察到HCC活检中HBx/MDM2/CXCR4/OV6轴上的任意两个指标的表达可预测乙型肝炎病毒相关HCC患者的预后。综上所述，我们的研究结果表明HBx在通过MDM2/CXCL12/CXCR4/β-连环蛋白信号轴调节HCC中OV6癌症干细胞的干细胞样特性方面的功能作用，并将HBx、MDM2、CXCR4和OV6确定为乙型肝炎病毒相关HCC患者一种新的预后途径和潜在治疗靶点。
