miR‐365 secreted from M2 Macrophage‐derived extracellular vesicles promotes pancreatic ductal adenocarcinoma progression through the BTG2/FAK/AKT axis

• Published in: Journal of cellular and molecular medicine Vol. 25; no. 10; pp. 4671 - 4683
• Main Authors: Li, Xin, Xu, Hao, Yi, Jianfeng, Dong, Chunlu, Zhang, Hui, Wang, Zhengfeng, Miao, Long, Zhou, Wence
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.05.2021; John Wiley and Sons Inc
• Subjects: Adenocarcinoma; Adenoviruses; AKT protein; Animals; Apoptosis; Beta cells; Bioinformatics; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; BTG2; BTG2 protein; Cancer; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell culture; cell invasion; Cell Proliferation; Experiments; Extracellular vesicles; Extracellular Vesicles - genetics; FAK/AKT pathway; Focal adhesion kinase; Focal Adhesion Kinase 1 - genetics; Focal Adhesion Kinase 1 - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; Kinases; Laboratory animals; Macrophages; Macrophages - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; MicroRNAs - genetics; microRNA‐365; miRNA; Original; Pancreas; Pancreatic cancer; pancreatic ductal adenocarcinoma; Pancreatic Neoplasms; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Protein-tyrosine kinase; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Tumor Cells, Cultured; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumorigenesis; Tumors; Xenograft Model Antitumor Assays; United States > US; China; BTG2; macrophages; extracellular vesicles; microRNA-365; FAK/AKT pathway; cell invasion; pancreatic ductal adenocarcinoma
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.16405

Clinical and experimental evidence indicates that tumour‐associated macrophages support cancer progression. Moreover, macrophage‐derived extracellular vesicles (EVs) are involved in pathogenesis of multiple cancers, yet the functions of molecular determinants in which have not been fully understood. Herein, we aim to understand whether macrophage modulates pancreatic ductal adenocarcinoma (PDAC) progression in an EV‐dependent manner and the underlying mechanisms. microRNA (miR)‐365 was experimentally determined to be enriched in the EVs from M2 macrophages (M2‐EVs), which could be transferred into PDAC cells. Using a co‐culture system, M2‐EVs could enhance the proliferating, migrating and invading potentials of PDAC cells, while inhibition of miR‐365 in M2‐EVs could repress these malignant functions. B‐cell translocation gene 2 (BTG2) was identified to be a direct target of miR‐365, while the focal adhesion kinase (F/ATP)‐dependent tyrosine kinase (AKT) pathway was activated by miR‐365. We further demonstrated that overexpression of BTG2 could delay the progression of PDAC in vitro, whereas by impairing BTG2‐mediated anti‐tumour effect, M2‐EV‐miR‐365 promoted PDAC progression. For validation, a nude mouse model of tumorigenesis was established, in which we found that targeting M2‐EV‐miR‐365 contributed to suppression of tumour growth. Collectively, M2‐EVs carry miR‐365 to suppress BTG2 expression, which activated FAK/AKT pathway, thus promoting PDAC development.