State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, 430071, Wuhan, China.
Department of Infectious Diseases, Renmin Hospital of Wuhan University, 430060, Wuhan, China.
Cell Oncol (Dordr). 2024 Oct;47(5):1757-1778. doi: 10.1007/s13402-024-00955-5. Epub 2024 May 16.
Chronic hepatitis B virus (HBV) infection is the primary risk factor for the malignant progression of hepatocellular carcinoma (HCC). It has been reported that HBV X protein (HBx) possesses oncogenic properties, promoting hepatocarcinogenesis and chemoresistance. However, the detailed molecular mechanisms are not fully understood. Here, we aim to investigate the effects of miR-128-3p/SPG21 axis on HBx-induced hepatocarcinogenesis and chemoresistance.
The expression of SPG21 in HCC was determined using bioinformatics analysis, quantitative real-time PCR (qRT-PCR), western blotting, and immunohistochemistry (IHC). The roles of SPG21 in HCC were elucidated through a series of in vitro and in vivo experiments, including real-time cellular analysis (RTCA), matrigel invasion assay, and xenograft mouse model. Pharmacologic treatment and flow cytometry were performed to demonstrate the potential mechanism of SPG21 in HCC.
SPG21 expression was elevated in HCC tissues compared to adjacent non-tumor tissues (NTs). Moreover, higher SPG21 expression correlated with poor overall survival. Functional assays revealed that SPG21 fostered HCC tumorigenesis and invasion. MiR-128-3p, which targeted SPG21, was downregulated in HCC tissues. Subsequent analyses showed that HBx amplified TRPM7-mediated calcium influx via miR-128-3p/SPG21, thereby activating the c-Jun N-terminal kinase (JNK) pathway. Furthermore, HBx inhibited doxorubicin-induced apoptosis by engaging the JNK pathway through miR-128-3p/SPG21.
The study suggested that SPG21, targeted by miR-128-3p, might be involved in enhancing HBx-induced carcinogenesis and doxorubicin resistance in HCC via the TRPM7/Ca/JNK signaling pathway. This insight suggested that SPG21 could be recognized as a potential oncogene, offering a novel perspective on its role as a prognostic factor and a therapeutic target in the context of HCC.
慢性乙型肝炎病毒（HBV）感染是肝细胞癌（HCC）恶性进展的主要危险因素。据报道，HBV X 蛋白（HBx）具有致癌特性，促进肝癌发生和化疗耐药。然而，其详细的分子机制尚不完全清楚。本研究旨在探讨 miR-128-3p/SPG21 轴对 HBx 诱导的肝癌发生和化疗耐药的影响。
通过生物信息学分析、实时定量 PCR（qRT-PCR）、western blot 和免疫组织化学（IHC）检测 SPG21 在 HCC 中的表达。通过一系列体外和体内实验，包括实时细胞分析（RTCA）、基质胶侵袭实验和异种移植小鼠模型，阐明 SPG21 在 HCC 中的作用。进行药物治疗和流式细胞术以证明 SPG21 在 HCC 中的潜在机制。
与相邻非肿瘤组织（NTs）相比，HCC 组织中 SPG21 的表达升高。此外，较高的 SPG21 表达与总生存期不良相关。功能分析显示 SPG21 促进 HCC 肿瘤发生和侵袭。miR-128-3p 靶向 SPG21，在 HCC 组织中下调。进一步分析表明，HBx 通过 miR-128-3p/SPG21 放大 TRPM7 介导的钙内流，从而激活 c-Jun N 端激酶（JNK）通路。此外，HBx 通过 miR-128-3p/SPG21 抑制阿霉素诱导的细胞凋亡，激活 JNK 通路。
该研究表明，miR-128-3p 靶向的 SPG21 可能通过 TRPM7/Ca/JNK 信号通路参与增强 HBx 诱导的 HCC 致癌作用和阿霉素耐药性。这一发现提示 SPG21 可能被认为是一种潜在的癌基因，为其作为 HCC 预后因素和治疗靶点的作用提供了新的视角。
