Chen Wei, Zhang Xiang, Zhang Bin, Chi Minhui, Zheng Qi
Department of Hepatology, Hepatology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian, China.
Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, Fujian, China.
Comb Chem High Throughput Screen. 2024 Jul 22. doi: 10.2174/0113862073306462240710174817.
The aim of this study is to explore the mechanism of HRAS and HSPB1 in ferroptosis. Primary liver cancer is the third leading cause of tumor death worldwide. Hepatocellular carcinoma (HCC) constitutes 75%-85% of cases of primary liver cancer. HRAS and HSPB1 co-express in multiple cells and participate in tumor progression regulation. However, their expression regulation and role in HCC have not been reported.
We investigated the effects of HRAS and HSPB1 on ferroptosis in in vitro experiments. Here, the role and mechanism of HRAS and HSPB1 on ferroptosis were investigated by transfecting the specific siRNA or overexpressing plasmids in HCC cells.
Bioinformatics analysis proved that HRAS and HSPB1 were highly expressed in HCC tissues and associated with poor prognosis of patients with HCC. In vitro, HRAS overexpression reduced the level of intracellular iron, ROS, and MDA production in HCC cells. Mechanistically, HRAS increased GPX4 expression and decreased the levels of ACSL4 and P53. HRAS also increased HSPB1 expression, and HRAS knockdown downregulated HSPB1 levels in HCC cells. Importantly, overexpression of HSPB1 reversed HRAS-increased concentration of iron, MDA, and ROS and eliminated HRAS-induced ferroptosis. Moreover, HRAS enhanced the proliferation and invasion by targeting HSPB1.
The regulation of HSPB1 by HRAS enhanced the resistance of HCC cells to ferroptosis. HRAS promoted proliferation and invasion by upregulating HSPB1. This research provides a new potential strategy for HCC treatment.
本研究旨在探讨HRAS和HSPB1在铁死亡中的作用机制。原发性肝癌是全球肿瘤死亡的第三大主要原因。肝细胞癌（HCC）占原发性肝癌病例的75%-85%。HRAS和HSPB1在多种细胞中共同表达，并参与肿瘤进展的调控。然而，它们在HCC中的表达调控及其作用尚未见报道。
我们在体外实验中研究了HRAS和HSPB1对铁死亡的影响。在此，通过在HCC细胞中转染特异性siRNA或过表达质粒，研究HRAS和HSPB1对铁死亡的作用及机制。
生物信息学分析证明，HRAS和HSPB1在HCC组织中高表达，且与HCC患者的不良预后相关。在体外，HRAS过表达降低了HCC细胞内铁、ROS和MDA的生成水平。机制上，HRAS增加了GPX4的表达，降低了ACSL4和P53的水平。HRAS还增加了HSPB1的表达，而HRAS敲低则下调了HCC细胞中HSPB1的水平。重要的是，HSPB1的过表达逆转了HRAS增加的铁、MDA和ROS浓度，并消除了HRAS诱导的铁死亡。此外，HRAS通过靶向HSPB1增强了增殖和侵袭能力。
HRAS对HSPB1的调控增强了HCC细胞对铁死亡的抗性。HRAS通过上调HSPB1促进增殖和侵袭。本研究为HCC治疗提供了一种新的潜在策略。
