文献类型：期刊文献

英文题名：Gastric cancer-derived exosomal let-7 g-5p mediated by SERPINE1 promotes macrophage M2 polarization and gastric cancer progression

作者：Ye, Zhenzhen[1,2,3];Yi, Jianfeng[2,3,4];Jiang, Xiangyan[1];Shi, Wengui[1,5];Xu, Hao[6];Cao, Hongtai[1];Qin, Long[1,5];Liu, Lixin[1,4];Wang, Tianming[2];Ma, Zhijian[1];Jiao, Zuoyi[1,5]

第一作者：Ye, Zhenzhen;叶蓁蓁

通信作者：Jiao, ZY[1];Jiao, ZY[2]

机构：[1]Lanzhou Univ, Hosp 2, Clin Med Sch 2, Dept Gen Surg, Lanzhou 730000, Gansu, Peoples R China;[2]Gansu Univ Chinese Med, Sch Clin Med 1, Lanzhou 730000, Gansu, Peoples R China;[3]Res Ctr Tradit Chinese Med, Lanzhou 730000, Gansu, Peoples R China;[4]Lanzhou Univ, Sch Clin Med 1, Lanzhou 730000, Gansu, Peoples R China;[5]Lanzhou Univ Second Hosp, Cuiying Biomed Res Ctr, Lanzhou, Gansu, Peoples R China;[6]Zhejiang Chinese Med Univ, Affiliated Hosp 1, Zhejiang Prov Hosp Chinese Med, Dept Hepatobiliary Surg, Hangzhou 310006, Zhejiang, Peoples R China

第一机构：Lanzhou Univ, Hosp 2, Clin Med Sch 2, Dept Gen Surg, Lanzhou 730000, Gansu, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ, Hosp 2, Clin Med Sch 2, Dept Gen Surg, Lanzhou 730000, Gansu, Peoples R China;[2]corresponding author), Lanzhou Univ Second Hosp, Cuiying Biomed Res Ctr, Lanzhou, Gansu, Peoples R China.

年份：2025

卷号：44

期号：1

外文期刊名：JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001389177200001)】；

基金：We sincerely thank Dr. Zhongtian Bai, Dr. Zeyuan Yu, Dr. Junhong Guan, and Dr. Jing Yang for their technical assistance and insightful feedback. We also extend our gratitude to Western Biotech, RiboBio Biotech, and HWayen Biotech for their support in mRNA-Seq, sRNA-Seq, and protein microarray analysis.

语种：英文

外文关键词：Gastric cancer; SERPINE1/PAI-1; let-7 g-5p; Cancer-derived exosome; M2 polarization

摘要：BackgroundTumor-associated macrophages (TAMs), particularly M2-polarized TAMs, are significant contributors to tumor progression, immune evasion, and therapy resistance in gastric cancer (GC). Despite efforts to target TAM recruitment or depletion, clinical efficacy remains limited. Consequently, the identification of targets that specifically inhibit or reprogram M2-polarized TAMs presents a promising therapeutic strategy.ObjectiveThis study aims to identify a dual-function target in GC cells that drives both malignant phenotypes and M2 macrophage polarization, revealing its molecular mechanisms to provide novel therapeutic targets for selectivly targeting M2-polarized TAMs in GC.MethodsTranscriptomic and clinical data from GC and adjacent tissues were utilized to identify mRNAs associated with high M2 macrophage infiltration and poor prognosis. Single-cell sequencing elucidated cell types expressing the target gene. Transwell co-culture and exosome intervention experiments demonstrated its role in M2 polarization. Small RNA sequencing of exosomes, western blotting, and CoIP assays revealed the molecular mechanisms underlying exosome-mediated M2 polarization. Protein array, ChIP and dual-luciferase reporter assays clarified the molecular mechanisms by which the target gene regulated exosomal miRNA. In vivo validation was performed using xenograft tumor models.ResultsSERPINE1 was identified as a highly expressed mRNA in GC tissues and cells, significantly associated with advanced clinical stages, worse prognosis, and higher M2 macrophage infiltration in patients with GC. SERPINE1 overexpression in GC cells promoted tumor growth and M2 macrophage polarization. SERPINE1 facilitated the transfer of let-7 g-5p to macrophages via cancer-derived exosomes, inducing M2 polarization. Exosomal let-7 g-5p internalized by macrophages downregulated SOCS7 protein levels, disrupting its interaction with STAT3 and relieving the inhibition of STAT3 phosphorylation, thereby leading to STAT3 hyperactivation, which consequently drove M2 polarization. Additionally, in GC cells, elevated SERPINE1 expression activated JAK2, enhancing STAT3 binding to the let-7 g-5p promoter and promoting its transcription, thereby increasing let-7 g-5p levels in exosomes.ConclusionGC cell-derived SERPINE1, functioning as a primary driver of GC growth and TAM M2 polarization, promotes M2 polarization through the regulation of exosomal let-7 g-5p transfer via autocrine activation of the JAK2/STAT3 signaling pathway. These findings elucidate a novel mechanism of SERPINE1-induced M2 polarization and highlight SERPINE1 as a promising target for advancing immunotherapy and targeted treatments in GC.