Integrin β6/Annexin A2 axis triggers autophagy to orchestrate hepatocellular carcinoma radioresistance

IF 13.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Death and Differentiation Pub Date : 2024-11-12 DOI:10.1038/s41418-024-01411-5
Ying Gao, Guangyan Wei, Hua Yu, Shuping Li, Yuhao Tang, Xin Yue, Yong Chen, Meixiao Zhan, Jian Wu
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Abstract

Radiotherapy (RT) is one of the main therapies for hepatocellular carcinoma (HCC), but its effectiveness has been constrained due to the resistance effect of radiation. Thus, the factors involved in radioresistance are evaluated and the underlying molecular mechanisms are also done. In this present study, we identified Integrin β6 (ITGB6) as a potential radioresistant gene through an integrative analysis of transcriptomic profiles, proteome datasets and survival using HCC cases treated with IR. We show that ITGB6 functionally contributed to radioresistance by activating autophagy through a series of in vitro and in vivo methods, such as clonogenic assays, autophagy flux (LC3B-GFP-mCherry reporter) analysis and a subcutaneous transplantation model. Mechanically, ITGB6 binds to Annexin A2 (ANXA2) and enhanced its stability by competitively antagonizing proteasome mediated ANXA2 degradation, thereby promoting autophagy and radioresistance. Notably, HCC radioresistance was significantly improved by either blocking ITGB6 or autophagy, but the combination was more effective. Importantly, ITGB6/ANXA2 axis triggered autophagic program endowed HCC cells with radioresistant activity in a radiated patient-derived xenograft (PDX) model and hydrodynamic injection in liver-specific Itgb6-knockout mice, further supported by clinical evidence. Together, our data revealed that ITGB6 is a radioresistant gene stabilizing the autophagy regulatory protein ANXA2, providing insights into the biological and potentially clinical significance of ITGB6/ANXA2 axis in radiotherapy planning of HCC.

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整合素β6/附件素A2轴触发自噬,协调肝细胞癌的放射抗性
放射治疗(RT)是治疗肝细胞癌(HCC)的主要疗法之一,但由于放射的抗药性效应,其有效性受到了限制。因此,我们对放射抗性的相关因素进行了评估,并对其潜在的分子机制进行了研究。在本研究中,我们利用接受过红外线治疗的 HCC 病例,通过对转录组图谱、蛋白质组数据集和存活率的综合分析,确定了 Integrin β6 (ITGB6) 是一种潜在的放射抗性基因。我们通过一系列体外和体内方法,如克隆形成试验、自噬通量(LC3B-GFP-mCherry报告物)分析和皮下移植模型,证明了ITGB6通过激活自噬在功能上促进了放射抗性。从机理上讲,ITGB6能与Annexin A2(ANXA2)结合,并通过竞争性拮抗蛋白酶体介导的ANXA2降解来增强其稳定性,从而促进自噬和放射抗性。值得注意的是,无论是阻断 ITGB6 还是自噬,都能显著改善 HCC 的放射抗性,但联合使用效果更好。重要的是,ITGB6/ANXA2 轴触发的自噬程序使 HCC 细胞在放射性患者异种移植(PDX)模型和肝特异性 Itgb6 基因敲除小鼠的水动力注射中具有抗放射活性,临床证据进一步证实了这一点。总之,我们的数据揭示了 ITGB6 是一种稳定自噬调控蛋白 ANXA2 的抗放射基因,为 ITGB6/ANXA2 轴在 HCC 放射治疗计划中的生物学意义和潜在临床意义提供了见解。
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来源期刊
Cell Death and Differentiation
Cell Death and Differentiation 生物-生化与分子生物学
CiteScore
24.70
自引率
1.60%
发文量
181
审稿时长
3 months
期刊介绍: Mission, vision and values of Cell Death & Differentiation: To devote itself to scientific excellence in the field of cell biology, molecular biology, and biochemistry of cell death and disease. To provide a unified forum for scientists and clinical researchers It is committed to the rapid publication of high quality original papers relating to these subjects, together with topical, usually solicited, reviews, meeting reports, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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