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
{"title":"Integrin β6/Annexin A2 axis triggers autophagy to orchestrate hepatocellular carcinoma radioresistance","authors":"Ying Gao, Guangyan Wei, Hua Yu, Shuping Li, Yuhao Tang, Xin Yue, Yong Chen, Meixiao Zhan, Jian Wu","doi":"10.1038/s41418-024-01411-5","DOIUrl":null,"url":null,"abstract":"<p>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 <i>Itgb6</i>-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.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"95 1","pages":""},"PeriodicalIF":13.7000,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death and Differentiation","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41418-024-01411-5","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

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.

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
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.
期刊最新文献
UGT8 mediated sulfatide synthesis modulates BAX localization and dictates apoptosis sensitivity of colorectal cancer A novel hypoxia-induced lncRNA, SZT2-AS1, boosts HCC progression by mediating HIF heterodimerization and histone trimethylation under a hypoxic microenvironment Polyol pathway-generated fructose is indispensable for growth and survival of non-small cell lung cancer KBTBD2 controls bone development by regulating IGF-1 signaling during osteoblast differentiation ACBP/DBI neutralization for the experimental treatment of fatty liver disease.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1