Silencing lncRNA HCG18 regulates GPX4-inhibited ferroptosis by adsorbing miR-450b-5p to avert sorafenib resistance in hepatocellular carcinoma.

IF 2.7 4区医学 Q3 TOXICOLOGY

Human & Experimental Toxicology Pub Date : 2023-01-01 DOI:10.1177/09603271221142818

Xiaoming Li, Yunhui Li, Peilong Lian, Qigang Lv, Fangfeng Liu

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引用次数: 9

Abstract

Ferroptosis is potential to relieve drug resistance in hepatocellular carcinoma (HCC). Glutathione peroxidase 4 (GPX4) is a critical modulator of ferroptosis. This study discussed the mechanism of GPX4-inhibited ferroptosis in sorafenib resistance in HCC. HCG18 in HCC cells was detected. Sorafenib resistant (SR) cell line Huh7-SR cells were treated with sorafenib (0, 2.5, 5, 7.5, 10 μM). After silencing HCG18 in Huh7-SR cells, cell activity, proliferation and apoptosis were detected. The levels of iron, the concentration of MDA, GSH and lipid reactive oxygen species (ROS) were measured to evaluate the ferroptosis. The downstream mechanism of HCG18 was predicted and verified. Huh7-SR cells were infected with lentivirus sh-HCG18 to establish xenograft tumor model. HCG18 was elevated in HCC cells and associated with sorafenib resistance. Silencing HCG18 inhibited cell proliferation, promoted apoptosis, and impaired sorafenib resistance. Ferroptosis was inhibited in Huh7-SR cells, while silencing HCG18 inhibited sorafenib resistance by promoting ferroptosis. GPX4 overexpression averted the promotion of sh-HCG18 on ferroptosis, thereby reducing sorafenib resistance. HCG18 sponged miR-450b-5p to regulate GPX4. Collectively, Silencing HCG18 inhibits GPX4 by binding to miR-450b-5p, promotes GPX4-inhibited ferroptosis, and averts sorafenib resistance in HCC.

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沉默lncRNA HCG18通过吸附miR-450b-5p来调节gpx4抑制的铁凋亡，从而避免肝癌中索拉非尼的耐药。

上睑下垂有可能减轻肝细胞癌(HCC)的耐药。谷胱甘肽过氧化物酶4 (GPX4)是铁下垂的关键调节剂。本研究探讨了gpx4抑制铁下垂在HCC索拉非尼耐药中的作用机制。检测HCC细胞中的HCG18。索拉非尼耐药(SR)细胞系Huh7-SR细胞分别用索拉非尼(0、2.5、5、7.5、10 μM)处理。在Huh7-SR细胞中沉默HCG18后，检测细胞活性、增殖和凋亡。测定铁、MDA、GSH和脂质活性氧(ROS)浓度，评价铁下垂程度。预测并验证了HCG18的下游机制。用慢病毒sh-HCG18感染Huh7-SR细胞，建立异种移植瘤模型。HCC细胞中HCG18升高并与索拉非尼耐药相关。沉默HCG18抑制细胞增殖，促进细胞凋亡，损害索拉非尼耐药性。在Huh7-SR细胞中，铁下垂被抑制，而沉默HCG18通过促进铁下垂抑制索拉非尼耐药。GPX4过表达避免了sh-HCG18对铁下垂的促进，从而降低了索拉非尼耐药性。HCG18海绵miR-450b-5p调节GPX4。总的来说，沉默HCG18通过与miR-450b-5p结合抑制GPX4，促进GPX4抑制的铁凋亡，并避免HCC中索拉非尼的耐药。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Human & Experimental Toxicology 医学-毒理学

CiteScore

5.70

自引率

3.60%

发文量

128

审稿时长

2.3 months

期刊介绍： Human and Experimental Toxicology (HET), an international peer reviewed journal, is dedicated to publishing preclinical and clinical original research papers and in-depth reviews that comprehensively cover studies of functional, biochemical and structural disorders in toxicology. The principal aim of the HET is to publish timely high impact hypothesis driven scholarly work with an international scope. The journal publishes on: Structural, functional, biochemical, and molecular effects of toxic agents; Studies that address mechanisms/modes of toxicity; Safety evaluation of novel chemical, biotechnologically-derived products, and nanomaterials for human health assessment including statistical and mechanism-based approaches; Novel methods or approaches to research on animal and human tissues (medical and veterinary patients) investigating functional, biochemical and structural disorder; in vitro techniques, particularly those supporting alternative methods