溶质载体家族7成员11-热休克蛋白B1轴：一种肝细胞癌进展和铁死亡调节的新机制。

SLC7A11-HSPB1 Axis: A Novel Mechanism for Hepatocellular Carcinoma Progression and Ferroptosis Regulation.

作者信息

An Yan, Liu Weilong, Deng Yuliang, Huang Wanqiu, Huang Jian

机构信息

Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China; Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200050, China.

Institute of Hepatology, National clinical research center for infectious diseases, Guangdong Key Lab for Diagnosis &Treatment of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, 518112, China.

出版信息

Biomed J. 2025 May 6:100869. doi: 10.1016/j.bj.2025.100869.

DOI:10.1016/j.bj.2025.100869

PMID:40339903

Abstract

BACKGROUND

SLC7A11, a plasma membrane protein, has been implicated as an oncogene in various cancers, including hepatocellular carcinoma (HCC). Its role in HCC pathogenesis, particularly in relation to ferroptosis, is not well understood. This study aims to investigate the function of SLC7A11 with ferroptosis and its interaction in development of HCC.

METHODS AND MATERIAL

Clinical HCC tissue samples were used to analyze the expression of SLC7A11 by RT-PCR. The impact of SLC7A11 on HCC cell viability, proliferation, and migration was assessed by CCK-8, AlamarBlue and Transwell. Protein-protein interactions were explored using co-immunoprecipitation and immunofluorescence. The effect of SLC7A11 on ferroptosis was evaluated by iron levels, ROS, and GSH. The impact of sorafenib and doxorubicin (DOX) on HCC cells was analyzed using cell viability assay.

RESULTS

SLC7A11 was found to be highly expressed in HCC tissues and was correlated with tumor size and poor prognosis. Overexpression of SLC7A11 in HCC cells promoted cell viability, proliferation, and migration. Additionally, SLC7A11 overexpression mitigated erastin-induced ferroptosis, as evidenced by decreased ROS levels and increased GSH levels. We also discovered that SLC7A11 interacted with HSPB1. HSPB1 inhibited erastin-induced ferroptosis. Furthermore, a portion of the cell death induced by sorafenib and DOX is attributed to ferroptosis, with HSPB1 and SLC7A11 inhibiting the death induced by the two drugs, respectively.

CONCLUSIONS

SLC7A11 plays a significant role in HCC progression by inhibiting ferroptosis, and its interaction with HSPB1 is a critical pathway in this process. Targeting the SLC7A11-HSPB1 axis may provide a novel therapeutic strategy for HCC treatment, highlighting the importance of understanding the mechanisms of ferroptosis in cancer cells.

摘要

背景

溶质载体家族7成员11（SLC7A11）是一种质膜蛋白，在包括肝细胞癌（HCC）在内的多种癌症中被认为是一种癌基因。其在HCC发病机制中的作用，特别是与铁死亡的关系，目前尚不清楚。本研究旨在探讨SLC7A11在铁死亡中的功能及其在HCC发生发展中的相互作用。

方法与材料

采用临床HCC组织样本，通过逆转录聚合酶链反应（RT-PCR）分析SLC7A11的表达。采用细胞计数试剂盒-8（CCK-8）、阿拉玛蓝（AlamarBlue）和Transwell实验评估SLC7A11对HCC细胞活力、增殖和迁移的影响。利用免疫共沉淀和免疫荧光技术探索蛋白质-蛋白质相互作用。通过铁水平、活性氧（ROS）和谷胱甘肽（GSH）评估SLC7A11对铁死亡的影响。使用细胞活力测定法分析索拉非尼和阿霉素（DOX）对HCC细胞的影响。

结果

发现SLC7A11在HCC组织中高表达，且与肿瘤大小和不良预后相关。HCC细胞中SLC7A11的过表达促进了细胞活力、增殖和迁移。此外，SLC7A11过表达减轻了埃拉斯汀诱导的铁死亡，表现为ROS水平降低和GSH水平升高。我们还发现SLC7A11与热休克蛋白B1（HSPB1）相互作用。HSPB1抑制埃拉斯汀诱导的铁死亡。此外，索拉非尼和DOX诱导的部分细胞死亡归因于铁死亡，HSPB1和SLC7A11分别抑制这两种药物诱导的细胞死亡。