Department of Biology and Chemistry, College of Sciences, National University of Defense Technology, Changsha 410073, China.
School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China.
Acta Biochim Biophys Sin (Shanghai). 2023 May 6;55(4):661-671. doi: 10.3724/abbs.2023076.
Despite substantial advances that have been made in understanding the etiology of hepatocellular carcinoma (HCC), the early-stage diagnosis and treatment of advanced-stage HCC remain a major challenge. RNF8, an E3 ligase important for the DNA damage response, has been proven to facilitate the progression of breast and lung cancer, but its role in HCC remains unclear. In this study, we find that the expression of RNF8 is up-regulated in HCC tissues and positively correlated with poor prognosis of HCC. Furthermore, silencing RNF8 by siRNAs attenuates the migration of HCC cells and inhibits epithelial-mesenchymal transition (EMT) by regulating the expressions of proteins including N-cadherin, β-catenin, snail, and ZO-1. Moreover, Kaplan‒Meier survival analysis shows that high RNF8 expression predicts poor survival benefits from sorafenib. Finally, cell viability assay demonstrates that RNF8 depletion enhances the sensitivity of HCC cells to sorafenib and lenvatinib treatment. We hypothesize that the inhibitory role of RNF8 in EMT and its enhancing effects on anti-cancer drugs orchestrate the protective effects of RNF8 deficiency in HCC, which indicates its potential in clinical application.
尽管在理解肝细胞癌（HCC）的病因学方面已经取得了重大进展，但早期诊断和治疗晚期 HCC 仍然是一个主要挑战。RNF8 是一种在 DNA 损伤反应中起重要作用的 E3 连接酶，已被证明可促进乳腺癌和肺癌的进展，但它在 HCC 中的作用尚不清楚。在这项研究中，我们发现 RNF8 的表达在 HCC 组织中上调，并与 HCC 的不良预后呈正相关。此外，通过 siRNAs 沉默 RNF8 可减弱 HCC 细胞的迁移，并通过调节 N-钙粘蛋白、β-连环蛋白、Snail 和 ZO-1 等蛋白的表达来抑制上皮-间充质转化（EMT）。此外，Kaplan-Meier 生存分析表明，高 RNF8 表达预示着索拉非尼治疗的生存获益不佳。最后，细胞活力测定表明 RNF8 耗竭增强了 HCC 细胞对索拉非尼和仑伐替尼治疗的敏感性。我们假设 RNF8 在 EMT 中的抑制作用及其对抗癌药物的增强作用可协调 RNF8 缺乏在 HCC 中的保护作用，这表明其在临床应用中的潜力。
