外泌体来源的 miR-210 通过 PTEN/PI3K/AKT 通路促进非小细胞肺癌迁移和侵袭。

MiR-210 in exosomes derived from CAFs promotes non-small cell lung cancer migration and invasion through PTEN/PI3K/AKT pathway.

机构信息

the First Department of Respiratory Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China.

Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China.

出版信息

Cell Signal. 2020 Sep;73:109675. doi: 10.1016/j.cellsig.2020.109675. Epub 2020 May 21.

DOI:10.1016/j.cellsig.2020.109675

PMID:32446904

Abstract

OBJECTIVE

Cancer-associated fibroblasts (CAFs) function as a crucial factor in tumor progression by carrying exosomes to neighboring cells. This study was assigned to expound the underlying mechanism of CAFs-derived exosomal miR-210 in non-small cell lung cancer (NSCLC) progression.

METHOD

CAFs and normal fibroblasts (NFs) were isolated and identified. Exosomes secreted from CAFs and NFs were isolated to analyze their effects on tumor volume and epithelial-mesenchymal transition (EMT). Exosomal miR-210 expression level was measured. The effects of exosomal miR-210 and UPF1 on cell viability, EMT, PTEN/PI3K/AKT signal pathway were determined. Dual-luciferase reporter gene assay was utilized to validate the binding of UPF1 to miR-210.

RESULTS

CAFs-derived exosomes (CAFs-exo) were successfully extracted and proven to be uptake by lung cancer cells. Up-regulated expression level of miR-210 was found in CAFs-exo, which was then proved to enhance cell migration, proliferation, invasion abilities and EMT in NSCLC cells. Overexpression of miR-210 can also inhibit UPF1 and PTEN, but activate the PTEN/PI3K/AKT pathway. UPF1 was a target gene of miR-210. MiR-210 can up-regulate UPF1 expression level to activate PTEN/PI3K/AKT pathway.

CONCLUSION

MiR-210 secreted by CAFs-exo could promote EMT by targeting UPF1 and activating PTEN/PI3K/AKT pathway, thereby promoting NSCLC migration and invasion.

摘要

目的

癌相关成纤维细胞（CAFs）通过向邻近细胞传递外泌体，成为肿瘤进展的关键因素。本研究旨在阐述 CAFs 来源的外泌体 miR-210 在非小细胞肺癌（NSCLC）进展中的潜在机制。

方法

分离并鉴定 CAFs 和正常成纤维细胞（NFs）。分离 CAFs 和 NFs 分泌的外泌体，分析其对肿瘤体积和上皮-间充质转化（EMT）的影响。检测外泌体 miR-210 的表达水平。测定外泌体 miR-210 和 UPF1 对细胞活力、EMT、PTEN/PI3K/AKT 信号通路的影响。利用双荧光素酶报告基因实验验证 UPF1 与 miR-210 的结合。

结果

成功提取并证实 CAFs 来源的外泌体（CAFs-exo）被肺癌细胞摄取。CAFs-exo 中 miR-210 的表达水平上调，进而证实其可增强 NSCLC 细胞的迁移、增殖、侵袭能力和 EMT。miR-210 的过表达还可以抑制 UPF1 和 PTEN，但激活 PTEN/PI3K/AKT 通路。UPF1 是 miR-210 的靶基因。miR-210 可以上调 UPF1 的表达水平，从而激活 PTEN/PI3K/AKT 通路。