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

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS

ACS Applied Bio Materials Pub Date : 2024-03-07 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: These findings 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。

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来源期刊

ACS Applied Bio Materials Chemistry-Chemistry (all)

CiteScore

9.40

自引率

2.10%

发文量

464