Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Cell Oncol (Dordr). 2024 Apr;47(2):639-655. doi: 10.1007/s13402-023-00889-4. Epub 2023 Oct 17.
As a vital component of the hepatitis B virus (HBV) nucleocapsid, HBV core protein (HBC) contributes to hepatocarcinogenesis. Here, we aimed to assess the effects of RANGAP1 and KDM2A on tumorigenesis induced by HBC.
Co-immunoprecipitation (Co-IP) combined with mass spectrometry were utilized to identify the proteins with the capacity to interact with HBC. The gene and protein levels of RANGAP1 and KDM2A in hepatocellular carcinoma (HCC) and HBV-positive HCC tissues were evaluated using different cohorts. The roles of RANGAP1 and KDM2A in HCC cells mediated by HBC were investigated in vitro and in vivo. Co-IP and western blot were used to estimate the interaction of HBC with RANGAP1 and KDM2A and assess RANGAP1 stabilization regulated by HBC.
We discovered that HBC could interact with RANGAP1 and KDM2A, the levels of which were markedly elevated in HCC tissues. Relying on RANGAP1 and KDM2A, HBC facilitated HCC cell growth and migration. The increased stabilization of RANGAP1 mediated by HBC was relevant to the disruption of the interaction between RANGAP1 and an E3 ligase SYVN1. RANGAP1 interacted with KDM2A, and it further promoted KDM2A stabilization by disturbing the interaction between KDM2A and SYVN1. HBC enhanced the interaction of KDM2A with RANGAP1 and upregulated the expression of KDM2A via RANGAP1 in HCC cells.
These findings demonstrate a novel mechanism by which HBC facilitates hepatocarcinogenesis. RANGAP1 and KDM2A could act as potential molecular targets for treating HBV-associated malignancy.
作为乙型肝炎病毒 (HBV) 核衣壳的重要组成部分，HBV 核心蛋白 (HBC) 有助于肝癌的发生。在这里，我们旨在评估 RANGAP1 和 KDM2A 对 HBC 诱导的肿瘤发生的影响。
使用免疫共沉淀 (Co-IP) 结合质谱技术鉴定与 HBC 相互作用的蛋白质。使用不同的队列评估 RANGAP1 和 KDM2A 在肝细胞癌 (HCC) 和 HBV 阳性 HCC 组织中的基因和蛋白水平。在体外和体内研究了 HBC 介导的 HCC 细胞中 RANGAP1 和 KDM2A 的作用。使用 Co-IP 和 Western blot 来评估 HBC 与 RANGAP1 和 KDM2A 的相互作用，并评估 HBC 调节的 RANGAP1 稳定。
我们发现 HBC 可以与 RANGAP1 和 KDM2A 相互作用，其水平在 HCC 组织中明显升高。依赖于 RANGAP1 和 KDM2A，HBC 促进 HCC 细胞的生长和迁移。HBC 介导的 RANGAP1 稳定性增加与 RANGAP1 与 E3 连接酶 SYVN1 之间的相互作用破坏有关。RANGAP1 与 KDM2A 相互作用，通过干扰 KDM2A 与 SYVN1 之间的相互作用，进一步促进 KDM2A 的稳定。HBC 通过 RANGAP1 增强了 KDM2A 与 RANGAP1 的相互作用，并上调了 HCC 细胞中 KDM2A 的表达。
这些发现揭示了 HBC 促进肝癌发生的新机制。RANGAP1 和 KDM2A 可以作为治疗 HBV 相关恶性肿瘤的潜在分子靶点。
