{"title":"细胞外囊泡包裹的ACSL4诱导肝细胞衰老,促进肝细胞癌进展","authors":"Pei-Pei Hou, Chong-Ming Zheng, Si-Hong Wu, Xi-Xiao Liu, Guang-Xin Xiang, Wei-Yang Cai, Gang Chen, Yong-Liang Lou","doi":"10.1158/0008-5472.CAN-24-0832","DOIUrl":null,"url":null,"abstract":"<p><p>Extracellular vesicles (EV) derived from cancer cells are crucial mediators of intercellular communication during tumor progression. The cargo in tumor-derived EVs that facilitates the establishment of a tumor-supportive microenvironment could serve as a therapeutic target to improve cancer treatment. Here, we demonstrated that hepatocellular carcinoma (HCC) cells secreted the acyl-CoA synthetase long-chain family member 4 (ACSL4) in large EVs (lEV) to modulate tumor-microenvironment interactions that promote HCC progression. HCC-derived lEV ACSL4 increased the intracellular abundance of polyunsaturated fatty acid-containing lipids and remodeled the lipid profile to potentiate lipid peroxidation in peritumoral hepatocytes, resulting in hepatocyte senescence accompanied by the senescence-associated secretory phenotype. Depletion of senescent hepatocytes by senolytic treatment suppressed tumor progression. In HCC cells, SREBP2-mediated transcriptional activation upregulated ACSL4 expression, and Akt-mediated phosphorylation of ACSL4 induced its packaging into lEVs by augmenting its interaction with Annexin A2. This study identified the critical regulatory function of ACSL4 secreted from HCC cells in inducing lipid remodeling and senescence in hepatocytes to support HCC progression, suggesting that targeting lEV ACSL4 is a potential therapeutic strategy for HCC. Significance: Peritumoral hepatocyte senescence mediated by ACSL4 secreted from hepatocellular carcinoma cells in extracellular vesicles promotes tumor progression through a senescence secretome and represents a therapeutic target in liver cancer.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"3953-3966"},"PeriodicalIF":12.5000,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Extracellular Vesicle-Packaged ACSL4 Induces Hepatocyte Senescence to Promote Hepatocellular Carcinoma Progression.\",\"authors\":\"Pei-Pei Hou, Chong-Ming Zheng, Si-Hong Wu, Xi-Xiao Liu, Guang-Xin Xiang, Wei-Yang Cai, Gang Chen, Yong-Liang Lou\",\"doi\":\"10.1158/0008-5472.CAN-24-0832\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Extracellular vesicles (EV) derived from cancer cells are crucial mediators of intercellular communication during tumor progression. The cargo in tumor-derived EVs that facilitates the establishment of a tumor-supportive microenvironment could serve as a therapeutic target to improve cancer treatment. Here, we demonstrated that hepatocellular carcinoma (HCC) cells secreted the acyl-CoA synthetase long-chain family member 4 (ACSL4) in large EVs (lEV) to modulate tumor-microenvironment interactions that promote HCC progression. HCC-derived lEV ACSL4 increased the intracellular abundance of polyunsaturated fatty acid-containing lipids and remodeled the lipid profile to potentiate lipid peroxidation in peritumoral hepatocytes, resulting in hepatocyte senescence accompanied by the senescence-associated secretory phenotype. Depletion of senescent hepatocytes by senolytic treatment suppressed tumor progression. In HCC cells, SREBP2-mediated transcriptional activation upregulated ACSL4 expression, and Akt-mediated phosphorylation of ACSL4 induced its packaging into lEVs by augmenting its interaction with Annexin A2. This study identified the critical regulatory function of ACSL4 secreted from HCC cells in inducing lipid remodeling and senescence in hepatocytes to support HCC progression, suggesting that targeting lEV ACSL4 is a potential therapeutic strategy for HCC. Significance: Peritumoral hepatocyte senescence mediated by ACSL4 secreted from hepatocellular carcinoma cells in extracellular vesicles promotes tumor progression through a senescence secretome and represents a therapeutic target in liver cancer.</p>\",\"PeriodicalId\":9441,\"journal\":{\"name\":\"Cancer research\",\"volume\":\" \",\"pages\":\"3953-3966\"},\"PeriodicalIF\":12.5000,\"publicationDate\":\"2024-12-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1158/0008-5472.CAN-24-0832\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/0008-5472.CAN-24-0832","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
源自癌细胞的胞外囊泡 (EV) 是肿瘤发展过程中细胞间交流的关键媒介。肿瘤衍生EVs中有助于建立肿瘤支持性微环境的载体可作为改善癌症治疗的治疗靶点。在这里,我们证实肝细胞癌(HCC)细胞在大细胞外囊泡(lEVs)中分泌酰基-CoA合成酶ACSL4,以调节肿瘤与微环境之间的相互作用,从而促进HCC的进展。HCC 源性 lEV ACSL4 增加了细胞内含多不饱和脂肪酸脂质的丰度,并重塑了脂质谱,从而增强了瘤周肝细胞的脂质过氧化,导致肝细胞衰老,并伴有衰老相关分泌表型(SASP)。通过溶酶治疗清除衰老肝细胞可抑制肿瘤的进展。在HCC细胞中,SREBP2介导的转录激活上调了ACSL4的表达,Akt介导的ACSL4磷酸化通过增强其与Annexin A2的相互作用诱导其包装成lEVs。这项研究确定了 HCC 细胞分泌的 ACSL4 在诱导肝细胞脂质重塑和衰老以支持 HCC 进展中的关键调控功能,表明针对 lEV 的 ACSL4 是一种潜在的 HCC 治疗策略。
Extracellular vesicles (EV) derived from cancer cells are crucial mediators of intercellular communication during tumor progression. The cargo in tumor-derived EVs that facilitates the establishment of a tumor-supportive microenvironment could serve as a therapeutic target to improve cancer treatment. Here, we demonstrated that hepatocellular carcinoma (HCC) cells secreted the acyl-CoA synthetase long-chain family member 4 (ACSL4) in large EVs (lEV) to modulate tumor-microenvironment interactions that promote HCC progression. HCC-derived lEV ACSL4 increased the intracellular abundance of polyunsaturated fatty acid-containing lipids and remodeled the lipid profile to potentiate lipid peroxidation in peritumoral hepatocytes, resulting in hepatocyte senescence accompanied by the senescence-associated secretory phenotype. Depletion of senescent hepatocytes by senolytic treatment suppressed tumor progression. In HCC cells, SREBP2-mediated transcriptional activation upregulated ACSL4 expression, and Akt-mediated phosphorylation of ACSL4 induced its packaging into lEVs by augmenting its interaction with Annexin A2. This study identified the critical regulatory function of ACSL4 secreted from HCC cells in inducing lipid remodeling and senescence in hepatocytes to support HCC progression, suggesting that targeting lEV ACSL4 is a potential therapeutic strategy for HCC. Significance: Peritumoral hepatocyte senescence mediated by ACSL4 secreted from hepatocellular carcinoma cells in extracellular vesicles promotes tumor progression through a senescence secretome and represents a therapeutic target in liver cancer.
期刊介绍:
Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research.
With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445.
Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.