{"title":"Exosome-Delivered EGFR Induced by Acidic Bile Salts Regulates Macrophage M2 Polarization to Promote Esophageal Adenocarcinoma Cell Proliferation","authors":"Chuangui Chen, Jinsheng Ding, Zhao Ma, Yongjie Xie, Linhua Zhang, Dunwan Zhu","doi":"10.2147/ott.s437560","DOIUrl":null,"url":null,"abstract":"<strong>Purpose:</strong> Chronic gastroesophageal reflux disease (GERD) causes the abnormal reflux of acid and bile salts, which would induce Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). EGFR, as one of main components of the exosome, plays an important role in cancer progression. Here, we investigated the role of acidic bile salts (ABS)-induced exosomal EGFR in EAC cell proliferation.<br/><strong>Methods:</strong> Electronic microscopic examination and Western blot were used to identify exosomes. Western blot, siRNA transfection, enzyme-linked immunosorbent assay, qRT-PCR, cell viability detection, mouse xenograft tumor models, and immunohistochemical staining were performed to study the function of ABS-induced exosomal EGFR in cell proliferation.<br/><strong>Results:</strong> We found that ABS improved the exosomal EGFR level of normal human esophageal epithelial cells, BE cells, and BE-associated adenocarcinoma cells. The results were confirmed in the serum-derived exosomes from healthy persons and patients suffering from GERD, BE with or without GERD, and EAC with or without GERD. Moreover, cell line-derived exosomal EGFR was found to promote macrophage M2 polarization through the PI3K-AKT pathway. The co-incubation medium of macrophages and exosomes improved cell proliferation and tumor growth, which depended on the exosomal EGFR level. CCL18 was identified as the most effective component of the co-incubation medium to promote EAC cell proliferation by binding to its receptor PITPNM3 in vitro and in vivo.<br/><strong>Conclusion:</strong> Our findings demonstrate that ABS-induced exosomal EGFR regulates macrophage M2 polarization to promote EAC proliferation. This study provides an important insight into the role of ABS in EAC development.<br/><br/><strong>Keywords:</strong> cancer progression, pro-oncogenic, PI3K/AKT pathway, CCL18, PITPNM3<br/>","PeriodicalId":19534,"journal":{"name":"OncoTargets and therapy","volume":null,"pages":null},"PeriodicalIF":2.7000,"publicationDate":"2024-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"OncoTargets and therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2147/ott.s437560","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: Chronic gastroesophageal reflux disease (GERD) causes the abnormal reflux of acid and bile salts, which would induce Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). EGFR, as one of main components of the exosome, plays an important role in cancer progression. Here, we investigated the role of acidic bile salts (ABS)-induced exosomal EGFR in EAC cell proliferation. Methods: Electronic microscopic examination and Western blot were used to identify exosomes. Western blot, siRNA transfection, enzyme-linked immunosorbent assay, qRT-PCR, cell viability detection, mouse xenograft tumor models, and immunohistochemical staining were performed to study the function of ABS-induced exosomal EGFR in cell proliferation. Results: We found that ABS improved the exosomal EGFR level of normal human esophageal epithelial cells, BE cells, and BE-associated adenocarcinoma cells. The results were confirmed in the serum-derived exosomes from healthy persons and patients suffering from GERD, BE with or without GERD, and EAC with or without GERD. Moreover, cell line-derived exosomal EGFR was found to promote macrophage M2 polarization through the PI3K-AKT pathway. The co-incubation medium of macrophages and exosomes improved cell proliferation and tumor growth, which depended on the exosomal EGFR level. CCL18 was identified as the most effective component of the co-incubation medium to promote EAC cell proliferation by binding to its receptor PITPNM3 in vitro and in vivo. Conclusion: Our findings demonstrate that ABS-induced exosomal EGFR regulates macrophage M2 polarization to promote EAC proliferation. This study provides an important insight into the role of ABS in EAC development.
Keywords: cancer progression, pro-oncogenic, PI3K/AKT pathway, CCL18, PITPNM3
期刊介绍:
OncoTargets and Therapy is an international, peer-reviewed journal focusing on molecular aspects of cancer research, that is, the molecular diagnosis of and targeted molecular or precision therapy for all types of cancer.
The journal is characterized by the rapid reporting of high-quality original research, basic science, reviews and evaluations, expert opinion and commentary that shed novel insight on a cancer or cancer subtype.
Specific topics covered by the journal include:
-Novel therapeutic targets and innovative agents
-Novel therapeutic regimens for improved benefit and/or decreased side effects
-Early stage clinical trials
Further considerations when submitting to OncoTargets and Therapy:
-Studies containing in vivo animal model data will be considered favorably.
-Tissue microarray analyses will not be considered except in cases where they are supported by comprehensive biological studies involving multiple cell lines.
-Biomarker association studies will be considered only when validated by comprehensive in vitro data and analysis of human tissue samples.
-Studies utilizing publicly available data (e.g. GWAS/TCGA/GEO etc.) should add to the body of knowledge about a specific disease or relevant phenotype and must be validated using the authors’ own data through replication in an independent sample set and functional follow-up.
-Bioinformatics studies must be validated using the authors’ own data through replication in an independent sample set and functional follow-up.
-Single nucleotide polymorphism (SNP) studies will not be considered.