SPG21, a potential oncogene targeted by miR-128-3p, amplifies HBx-induced carcinogenesis and chemoresistance via activation of TRPM7-mediated JNK pathway in hepatocellular carcinoma.

IF 4.9 2区医学 Q2 CELL BIOLOGY

Cellular Oncology Pub Date : 2024-10-01 Epub Date: 2024-05-16 DOI:10.1007/s13402-024-00955-5

Ping Zhou, Wei Yao, Lijuan Liu, Qiujin Yan, Xiaobei Chen, Xiaocui Wei, Shuang Ding, Zhao Lv, Fan Zhu

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Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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/Ca²⁺/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.

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SPG21是miR-128-3p靶向的潜在癌基因，它通过激活TRPM7介导的肝细胞癌JNK通路，扩大了HBx诱导的癌变和化疗耐药性。

目的：慢性乙型肝炎病毒（HBV）感染是肝细胞癌（HCC）恶性进展的主要风险因素。据报道，HBV X 蛋白（HBx）具有致癌特性，可促进肝癌的发生和化疗耐药性。然而，详细的分子机制尚未完全明了。在此，我们旨在研究 miR-128-3p/SPG21 轴对 HBx 诱导的肝癌发生和化疗耐药性的影响：方法：采用生物信息学分析、定量实时 PCR（qRT-PCR）、Western 印迹和免疫组化（IHC）等方法测定 SPG21 在 HCC 中的表达。通过一系列体内外实验，包括实时细胞分析（RTCA）、matrigel侵袭实验和异种移植小鼠模型，阐明了SPG21在HCC中的作用。通过药物治疗和流式细胞术证明了SPG21在HCC中的潜在作用机制：结果：与邻近的非肿瘤组织（NTs）相比，SPG21在HCC组织中的表达升高。此外，较高的 SPG21 表达与较差的总生存率相关。功能测试显示 SPG21 促进了 HCC 的肿瘤发生和侵袭。针对 SPG21 的 MiR-128-3p 在 HCC 组织中被下调。随后的分析表明，HBx通过miR-128-3p/SPG21扩大了TRPM7介导的钙离子流入，从而激活了c-Jun N-末端激酶（JNK）通路。此外，HBx 通过 miR-128-3p/SPG21 参与 JNK 通路，抑制了多柔比星诱导的细胞凋亡：该研究表明，miR-128-3p靶向的SPG21可能通过TRPM7/Ca2+/JNK信号通路参与增强HBx诱导的癌变和多柔比星在HCC中的抗性。这一发现表明 SPG21 可被视为一种潜在的癌基因，为其在 HCC 中作为预后因素和治疗靶点的作用提供了新的视角。

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来源期刊

Cellular Oncology ONCOLOGY-CELL BIOLOGY

CiteScore

10.30

自引率

1.50%

发文量

审稿时长

12 months

期刊介绍： The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.