HAND2-AS1 Promotes Ferroptosis to Reverse Lenvatinib Resistance in Hepatocellular Carcinoma by TLR4/NOX2/DUOX2 Axis.

IF 2.3 4区医学 Q3 ONCOLOGY

Current cancer drug targets Pub Date : 2025-01-01 DOI:10.2174/0115680096279597240219055135

Zheng Song, Yu Zhang, Wei Luo, Chao Sun, Caihong Lv, Sihao Wang, Quanwei He, Ran Xu, Zhaofang Bai, Xiujuan Chang, Yongping Yang

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引用次数: 0

Abstract

Introduction: Lenvatinib resistance causes less than 40% of the objective response rate. Therefore, it is urgent to explore new therapeutic targets to reverse the lenvatinib resistance for HCC. HAND2-AS1 is a critical tumor suppressor gene in various cancers.

Methods: Here, we investigated the role of HAND2-AS1 in the molecular mechanism of lenvatinib resistance in HCC. It was found that HAND2-AS1 was lowly expressed in the HepG2 lenvatinib resistance (HepG2-LR) cells and HCC tissues and associated with progression-free intervals via TCGA. Overexpression of HAND2-AS1 (OE-HAND2-AS1) decreased the IC₅₀ of lenvatinib in HepG2-LR cells to reverse lenvatinib resistance. Moreover, OE-HAND2-AS1 induced intracellular concentrations of malondialdehyde (MDA) and lipid ROS and decreased the ratio of glutathione to glutathione disulfide (GSH/GSSG) to promote ferroptosis.

Results: A xenograft model in which nude mice were injected with OE-HAND2-AS1 HepG2-LR cells confirmed that OE-HAND2-AS1 could reverse lenvatinib resistance and decrease tumor formation in vivo. HAND2-AS1 promoted the expression of ferroptosis-related genes (TLR4, NOX2, and DUOX2) and promoted ferroptosis to reverse lenvatinib resistance by increasing TLR4/ NOX2/DUOX2 via competing endogenous miR-219a-1-3p in HCC cells. Besides, patients with a low HAND2-AS1 level had early recurrence after resection.

Conclusion: HAND2-AS1 promotes ferroptosis in HCC cells and reverses lenvatinib resistance by regulating TLR4/NOX2/DUOX2 axis. It suggested that HAND2-AS1 may be a potential therapeutic target and an indicator of early recurrence for HCC.

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HAND2-AS1通过TLR4/NOX2/DUOX2轴促进铁凋亡以逆转肝细胞癌的伦伐替尼抗性

简介来伐替尼耐药导致的客观应答率不足40%。因此，探索逆转来伐替尼耐药的新治疗靶点已迫在眉睫。方法：我们研究了HAND2-AS1在来伐替尼耐药分子机制中的作用。通过TCGA发现，HAND2-AS1在HepG2来伐替尼耐药（HepG2-LR）细胞和HCC组织中低表达，并与无进展间隔期相关。过表达HAND2-AS1（OE-HAND2-AS1）可降低来伐替尼在HepG2-LR细胞中的IC50，从而逆转来伐替尼耐药。此外，OE-HAND2-AS1还能诱导细胞内丙二醛（MDA）和脂质ROS的浓度，并降低谷胱甘肽与谷胱甘肽二硫化物（GSH/GSSG）的比率，从而促进铁变态反应：结果：裸鼠注射OE-HAND2-AS1 HepG2-LR细胞的异种移植模型证实，OE-HAND2-AS1可逆转来伐替尼耐药性并减少体内肿瘤的形成。HAND2-AS1通过竞争HCC细胞中的内源性miR-219a-1-3p，促进铁变态反应相关基因（TLR4、NOX2和DUOX2）的表达，并通过增加TLR4/ NOX2/DUOX2促进铁变态反应，从而逆转来伐替尼耐药。此外，HAND2-AS1水平较低的患者切除后复发较早：这些研究结果表明，HAND2-AS1可能是潜在的治疗靶点，也是HCC早期复发的指标。

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

Current cancer drug targets 医学-肿瘤学

CiteScore

5.40

自引率

0.00%

发文量

105

审稿时长

1 months

期刊介绍： Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes and genes. Current Cancer Drug Targets publishes original research articles, letters, reviews / mini-reviews, drug clinical trial studies and guest edited thematic issues written by leaders in the field covering a range of current topics on drug targets involved in cancer. As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.