The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road Shanghai, Shanghai, 200438, China.
Center for Health Research, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou, 510530, China.
Cell Death Dis. 2022 May 9;13(5):446. doi: 10.1038/s41419-022-04895-6.
DNA methylation plays a pivotal role in the development and progression of tumors. However, studies focused on the dynamic changes of DNA methylation in the development of hepatocellular carcinoma (HCC) are rare. To systematically illustrate the dynamic DNA methylation alternation from premalignant to early-stage liver cancer with the same genetic background, this study enrolled 5 HBV-related patients preceded with liver cirrhosis, pathologically identified as early-stage HCC with dysplastic nodules. Liver fibrosis tissues, dysplastic nodules and early HCC tissues from these patients were used to measure DNA methylation. Here, we report significant differences in the DNA methylation spectrum among the three types of tissues. In the early stage of HCC, DNA hypermethylation of tumor suppressor genes is predominant. Additionally, DNA hypermethylation in the early stage of HCC changes the binding ability of transcription factor TP53 to the promoter of tumor suppressor gene ZNF334, and inhibits the expression of ZNF334 at the transcription level. Furthermore, through a series of in vivo and in vitro experiments, we have clarified the exacerbation effect of tumor suppressor gene ZNF334 deletion in the occurrence of HCC. Combined with clinical data, we found that the overall survival and relapse-free survival of patients with high ZNF334 expression are significantly longer. Thus, we partly elucidated a sequential alternation of DNA methylation modification during the occurrence of HCC, and clarified the biological function and regulatory mechanism of the tumor suppressor gene ZNF334, which is regulated by related DNA methylation sites. Our study provides a new target and clinical evidence for the early diagnosis and sheds light on the precise treatment of liver cancer.
DNA 甲基化在肿瘤的发生和发展中起着关键作用。然而，关于 DNA 甲基化在肝细胞癌（HCC）发生过程中的动态变化的研究很少。为了系统地阐明具有相同遗传背景的从癌前病变到早期肝癌的动态 DNA 甲基化改变，本研究纳入了 5 例 HBV 相关的肝硬化患者，这些患者的病理诊断为早期 HCC 伴异型增生结节。使用这些患者的肝纤维化组织、异型增生结节和早期 HCC 组织来测量 DNA 甲基化。在这里，我们报告了这三种组织中 DNA 甲基化谱的显著差异。在 HCC 的早期阶段，肿瘤抑制基因的 DNA 高甲基化占主导地位。此外，早期 HCC 中的 DNA 高甲基化改变了转录因子 TP53 与肿瘤抑制基因 ZNF334 启动子的结合能力，并抑制了 ZNF334 在转录水平的表达。此外，通过一系列体内和体外实验，我们阐明了肿瘤抑制基因 ZNF334 缺失在 HCC 发生中的加重作用。结合临床资料，我们发现高 ZNF334 表达患者的总生存率和无复发生存率显著延长。因此，我们部分阐明了 HCC 发生过程中 DNA 甲基化修饰的顺序改变，并阐明了受相关 DNA 甲基化位点调控的肿瘤抑制基因 ZNF334 的生物学功能和调控机制。我们的研究为早期诊断提供了新的靶点和临床证据，并为肝癌的精准治疗提供了思路。
