Ding Yi-Hong, Huang Tian-Yi, Xu Shi-Meng, Li Min, Shi Xiang, Sun Wen-Yan, Lu Cui-Hua, Liu Zhao-Xiu, Huang Wei
Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.
Department of Gastroenterology, The People's Hospital of Rugao, Nantong, China.
Transl Cancer Res. 2025 Aug 31;14(8):4939-4954. doi: 10.21037/tcr-2024-2319. Epub 2025 Aug 18.
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality with limited therapeutic options. Solute carrier family 25 member 10 (SLC25A10), a mitochondrial transporter linked to metabolic regulation and tumor progression, has unclear roles in HCC pathogenesis. This study aimed to elucidate the functional and mechanistic contributions of SLC25A10 to HCC development.
The International Cancer Genome Consortium (ICGC) database, GAO dataset, quantitative real-time polymerase chain reaction (qRT-PCR), western blot (WB), and immunohistochemistry (IHC) staining were used to explore the expression levels of SLC25A10 in HCC tissues and cell lines. Functional assays [cell counting kit-8, colony formation, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, SA-β-galactosidase staining, and flow cytometry] and a subcutaneous xenograft mouse model were employed to assess the effects of SLC25A10 knockdown on proliferation, senescence, and tumorigenesis. Finally, NecroX-7, a high mobility group box 1 (HMGB1) inhibitor, was used to delineate the underlying molecular mechanisms involved in cell senescence caused by SLC25A10 knockdown.
The protein and messenger RNA (mRNA) levels of SLC25A10 in HCC tissues were higher than those in adjacent normal tissues. Knockdown of SLC25A10 suppressed cell proliferation, induced senescence-associated β-galactosidase activity, and triggered G1 phase arrest by downregulating cyclin-dependent kinase 4 ()/ and upregulating cyclin-dependent kinase inhibitor 2A (). , SLC25A10 silencing reduced tumor growth and decreased KI67/proliferating cell nuclear antigen (PCNA) expression, while enhancing HMGB1, a senescence-associated secretory phenotype (SASP) marker. Mechanically, pharmacological inhibition of HMGB1 with NecroX-7 partially reversed the anti-proliferative and pro-senescent effects of SLC25A10 knockdown, restoring cell cycle progression.
SLC25A10 promotes HCC progression by suppressing cellular senescence. Pharmacological or genetic inhibition of SLC25A10 triggers tumor suppression through HMGB1-mediated SASP signaling, positioning SLC25A10 as a promising therapeutic target for HCC intervention.
肝细胞癌（HCC）仍然是癌症相关死亡的主要原因，治疗选择有限。溶质载体家族25成员10（SLC25A10）是一种与代谢调节和肿瘤进展相关的线粒体转运蛋白，在HCC发病机制中的作用尚不清楚。本研究旨在阐明SLC25A10对HCC发展的功能和机制贡献。
利用国际癌症基因组联盟（ICGC）数据库、GAO数据集、定量实时聚合酶链反应（qRT-PCR）、蛋白质印迹法（WB）和免疫组织化学（IHC）染色来探究SLC25A10在HCC组织和细胞系中的表达水平。采用功能测定法[细胞计数试剂盒-8、集落形成、5-乙炔基-2'-脱氧尿苷（EdU）掺入、SA-β-半乳糖苷酶染色和流式细胞术]以及皮下异种移植小鼠模型来评估SLC25A10敲低对增殖、衰老和肿瘤发生的影响。最后，使用高迁移率族蛋白B1（HMGB1）抑制剂NecroX-7来阐明SLC25A10敲低导致细胞衰老所涉及的潜在分子机制。
HCC组织中SLC25A10的蛋白质和信使核糖核酸（mRNA）水平高于相邻正常组织。敲低SLC25A10可抑制细胞增殖，诱导衰老相关β-半乳糖苷酶活性，并通过下调细胞周期蛋白依赖性激酶4（CDK4）/细胞周期蛋白D1（Cyclin D1）和上调细胞周期蛋白依赖性激酶抑制剂2A（p21）触发G1期阻滞。此外，SLC25A10沉默可降低肿瘤生长并降低KI67/增殖细胞核抗原（PCNA）表达，同时增强HMGB1（一种衰老相关分泌表型（SASP）标志物）的表达。在机制上，用NecroX-7对HMGB1进行药理抑制可部分逆转SLC25A10敲低的抗增殖和促衰老作用，恢复细胞周期进程。
SLC25A10通过抑制细胞衰老促进HCC进展。对SLC25A10的药理或基因抑制通过HMGB1介导的SASP信号传导触发肿瘤抑制，将SLC25A10定位为HCC干预的有前景的治疗靶点。
