Lung CSC-derived exosomal miR-210-3p contributes to a pro-metastatic phenotype in lung cancer by targeting FGFRL1.

Li Wang,Haoyue Hu,Yanyang Liu,Zhen Sun,Li Tu,Feng Luo,Jun He

doi:10.1111/jcmm.15274

Abstract

Lung cancer has the highest mortality rate among human cancers, and the majority of deaths can be attributed to metastatic spread. Lung cancer stem cells (CSCs) are a component of the tumour microenvironment that contributes to this process. Exosomes are small membrane vesicles secreted by all types of cells that mediate cell interactions, including cancer metastasis. Here, we show that lung CSC‐derived exosomes promote the migration and invasion of lung cancer cells, up‐regulate expression levels of N‐cadherin, vimentin, MMP‐9 and MMP‐1, and down‐regulate E‐cadherin expression. Moreover, we verified that these exosomes contribute to a pro‐metastatic phenotype in lung cancer cells via miR‐210‐3p transfer. The results of bioinformatics analysis and dual‐luciferase reporter assays further indicated that miR‐210‐3p may bind to fibroblast growth factor receptor‐like 1 (FGFRL1); silencing FGFRL1 enhanced the metastatic ability of lung cancer cells, whereas overexpressing FGFRL1 suppressed metastasis. Taken together, our results provide new insights into a potential molecular mechanism whereby lung CSC‐derived exosomal miR‐210‐3p targets FGFRL1 to promote lung cancer metastasis. FGFRL1 may be a promising therapeutic target in lung cancer.

Highlights

According to cancer statistics published in 2018, lung cancer is a leading cause of cancer-associated morbidity and mortality worldwide.[1]
The results of the Transwell assays performed in this study showed that the number of migrated or invaded cells derived from tumour spheres was greatly increased, compared to the number of migrated or invaded cells derived from parental A549 cells (Figure 1G-H)
The tumour spheres derived from parental A549 cells overexpressed stemness-associated markers including CD133, Nanog, Sox[2] and ALDH1, which are associated with the lung cancer stem cells (CSCs) phenotype.[23,24]

Summary

| INTRODUCTION

According to cancer statistics published in 2018, lung cancer is a leading cause of cancer-associated morbidity and mortality worldwide.[1]. Previous studies have suggested that lung CSCs may be isolated and enriched from surgically resected tumour tissue or lung cancer cell lines such as A549, PC-9 and H460.15,16 These cells display obvious morphological differences from their parental lung cancer cells and express a stemness phenotype that includes enhanced ability for self-renewal, resistance to chemo/radiotherapy, high expression of stemness-associated markers such as CD133, ALDH1, Sox[2] and Nanog, and increased metastatic potential Due to these specific features, lung CSCs were considered to be the main mediators of lung cancer metastasis and recurrence.[17] One recent study of renal carcinoma showed that CSC-derived exosomes promoted EMT in renal carcinoma cells by transferring miR-19b-3p.18.

| MATERIALS AND METHODS

Findings

| DISCUSSION