Therapy-induced senescent tumor cell-derived extracellular vesicles promote colorectal cancer progression through SERPINE1-mediated NF-κB p65 nuclear translocation

作者全名："Zhang, Dan; Zhang, Jian-Wei; Xu, Hui; Chen, Xin; Gao, Yu; Jiang, Huan-Gang; Wang, You; Wu, Han; Yang, Lei; Wang, Wen-Bo; Dai, Jing; Xia, Ling; Peng, Jin; Zhou, Fu-Xiang"

作者地址："[Zhang, Dan; Xu, Hui; Chen, Xin; Gao, Yu; Jiang, Huan-Gang; Wang, You; Wu, Han; Yang, Lei; Wang, Wen-Bo; Dai, Jing; Xia, Ling; Peng, Jin; Zhou, Fu-Xiang] Wuhan Univ, Zhongnan Hosp, Dept Radiat & Med Oncol, Wuhan 430071, Hubei, Peoples R China; [Zhang, Dan; Xu, Hui; Chen, Xin; Gao, Yu; Jiang, Huan-Gang; Wang, You; Wu, Han; Yang, Lei; Wang, Wen-Bo; Dai, Jing; Xia, Ling; Peng, Jin; Zhou, Fu-Xiang] Wuhan Univ, Zhongnan Hosp, Hubei Key Lab Tumor Biol Behav, Wuhan, Peoples R China; [Zhang, Dan; Xu, Hui; Chen, Xin; Gao, Yu; Jiang, Huan-Gang; Wang, You; Wu, Han; Yang, Lei; Wang, Wen-Bo; Dai, Jing; Xia, Ling; Peng, Jin; Zhou, Fu-Xiang] Wuhan Univ, Zhongnan Hosp, Hubei Clin Canc Study Ctr, Wuhan, Peoples R China; [Zhang, Jian-Wei] Chongqing Med Univ, Dept Gastroenterol, Affiliated Hosp 1, Chongqing, Peoples R China"

通信作者："Peng, J; Zhou, FX (通讯作者)，Wuhan Univ, Zhongnan Hosp, Dept Radiat & Med Oncol, Wuhan 430071, Hubei, Peoples R China.; Peng, J; Zhou, FX (通讯作者)，Wuhan Univ, Zhongnan Hosp, Hubei Key Lab Tumor Biol Behav, Wuhan, Peoples R China.; Peng, J; Zhou, FX (通讯作者)，Wuhan Univ, Zhongnan Hosp, Hubei Clin Canc Study Ctr, Wuhan, Peoples R China."

来源：MOLECULAR CANCER

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001197174000002

JCR分区：Q1

影响因子：37.3

年份：2024

卷号：23

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Cellular senescence; Extracellular vesicles; Colorectal cancer; SERPINE1; p65

摘要："Background Cellular senescence frequently occurs during anti-cancer treatment, and persistent senescent tumor cells (STCs) unfavorably promote tumor progression through paracrine secretion of the senescence-associated secretory phenotype (SASP). Extracellular vesicles (EVs) have recently emerged as a novel component of the SASP and primarily mediate the tumor-promoting effect of the SASP. Of note, the potential effect of EVs released from STCs on tumor progression remains largely unknown.Methods We collected tumor tissues from two cohorts of colorectal cancer (CRC) patients to examine the expression of p16, p21, and SERPINE1 before and after anti-cancer treatment. Cohort 1 included 22 patients with locally advanced rectal cancer (LARC) who received neoadjuvant therapy before surgical resection. Cohort 2 included 30 patients with metastatic CRC (mCRC) who received first-line irinotecan-contained treatment. CCK-8, transwell, wound-healing assay, and tumor xenograft experiments were carried out to determine the impacts of EVs released from STCs on CRC progression in vitro and in vivo. Quantitative proteomic analysis was applied to identify protein cargo inside EVs secreted from STCs. Immunoprecipitation and mass spectrometer identification were utilized to explore the binding partners of SERPINE1. The interaction of SERPINE1 with p65 was verified by co-immunoprecipitation, and their co-localization was confirmed by immunofluorescence.Results Chemotherapeutic agents and irradiation could potently induce senescence in CRC cells in vitro and in human CRC tissues. The more significant elevation of p16 and p21 expression in patients after anti-cancer treatment displayed shorter disease-free survival (DFS) for LARC or progression-free survival (PFS) for mCRC. We observed that compared to non-STCs, STCs released an increased number of EVs enriched in SERPINE1, which further promoted the progression of recipient cancer cells. Targeting SERPINE1 with a specific inhibitor, tiplaxtinin, markedly attenuated the tumor-promoting effect of STCs-derived EVs. Additionally, the patients with greater increment of SERPINE1 expression after anti-cancer treatment had shorter DFS for LARC or PFS for mCRC. Mechanistically, SERPINE1 bound to p65, promoting its nuclear translocation and subsequently activating the NF-kappa B signaling pathway.Conclusions We provide the in vivo evidence of the clinical prognostic implications of therapy-induced senescence. Our results revealed that STCs were responsible for CRC progression by producing large amounts of EVs enriched in SERPINE1. These findings further confirm the crucial role of therapy-induced senescence in tumor progression and offer a potential therapeutic strategy for CRC treatment."

基金机构："Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission"

基金资助正文：Not applicable.