Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, China.
Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, 710032, Xi'an, China.
Oncogene. 2019 Jun;38(24):4804-4819. doi: 10.1038/s41388-019-0759-9. Epub 2019 Feb 25.
Hepatitis B virus (HBV) infection is the primary cause of hepatocellular carcinoma (HCC). Zinc-finger protein 382 (ZNF382), which belongs to zinc-finger protein family, has been documented to be downregulated in certain types of cancer. However, its role in HCC remains largely unknown. In this study, we demonstrated that ZNF382 expression was significantly elevated in HBV-infected liver cirrhosis tissues relative to HBV-negative normal liver tissues at protein levels, but not at mRNA levels, and was positively correlated with the levels of HBV DNA and hepatitis B virus X protein (HBx). Further studies revealed that ZNF382 was a target of miR-6867, and HBx promoted the translation of ZNF382 during HBV chronic infection through Erk-mediated miR-6867 inhibition. In addition, our data showed that ZNF382 was frequently downregulated by promoter methylation in HBV-related HCCs relative to HBV-infected liver cirrhosis tissues, and decreased expression of ZNF382 was strongly correlated with poor survival in early-stage HCC patients. Functional studies demonstrated that ZNF382 was a potent tumor suppressor in HCC cells through inhibiting cell proliferation, colony formation, migration, invasion, and tumorigenic potential in nude mice, and inducing cell apoptosis. Mechanistically, ZNF382 exerted its tumor-suppressor functions in HCC through transcriptionally repressing its downstream targets such as Fos proto-oncogene (FOS), Jun proto-oncogene (JUN), disheveled segment polarity protein 2 (DVL2), and frizzled class receptor 1 (FZD1), thereby impairing the activities of activating protein 1 (AP-1) and Wnt/β-catenin pathways and activating p53 signaling. Altogether, our data show that ZNF382 acts as a tumor suppressor, and is co-regulated by HBx and epigenetic mechanism in HBV-related hepatocellular carcinogenesis.
乙型肝炎病毒 (HBV) 感染是肝细胞癌 (HCC) 的主要病因。锌指蛋白 382 (ZNF382) 属于锌指蛋白家族，其在某些类型的癌症中表达下调已有报道。然而，其在 HCC 中的作用仍知之甚少。在这项研究中，我们发现在蛋白水平上，HBV 感染的肝硬化组织中 ZNF382 的表达明显高于 HBV 阴性的正常肝组织，但在 mRNA 水平上没有差异，且与 HBV DNA 和乙型肝炎病毒 X 蛋白 (HBx) 的水平呈正相关。进一步的研究表明，ZNF382 是 miR-6867 的靶标，HBx 通过 Erk 介导的 miR-6867 抑制促进 ZNF382 在 HBV 慢性感染期间的翻译。此外，我们的数据表明，相对于 HBV 感染的肝硬化组织，HBV 相关 HCC 中 ZNF382 常因启动子甲基化而下调，且 ZNF382 表达降低与早期 HCC 患者的不良生存密切相关。功能研究表明，ZNF382 通过抑制 HCC 细胞的增殖、集落形成、迁移、侵袭和裸鼠肿瘤形成能力，以及诱导细胞凋亡，在 HCC 细胞中发挥强效的肿瘤抑制作用。机制上，ZNF382 通过转录抑制其下游靶标，如 Fos 原癌基因 (FOS)、Jun 原癌基因 (JUN)、卷曲蛋白结构域蛋白 2 (DVL2) 和卷曲蛋白受体 1 (FZD1)，从而抑制激活蛋白 1 (AP-1) 和 Wnt/β-连环蛋白信号通路的活性，发挥其肿瘤抑制功能。总之，我们的数据表明，ZNF382 作为一种肿瘤抑制因子，在 HBV 相关的肝细胞癌发生中受 HBx 和表观遗传机制的共同调控。
