Mex3a interacts with LAMA2 to promote lung adenocarcinoma metastasis via PI3K/AKT pathway

Jinghui Liang,Zhenguo Sun,Jin Jiang,Hui Tian,Zitong Feng,Yongmeng Li,Renchang Zhao,Jiang Wang,Haixia Li,Jingyi Han,Bin Lv

doi:10.1038/s41419-020-02858-3

Abstract

Lung adenocarcinoma (LUAD) is the main subtype of lung cancer. In this study, we found that RBP Mex3a was significantly upregulated in LUAD tissues and elevated Mex3a expression was associated with poor LUAD prognosis and metastasis. Furthermore, we demonstrated that Mex3a knockdown significantly inhibited LUAD cell migration and invasion in vitro and metastasis in nude mice. Transcriptome sequencing indicated that Mex3a affected gene expression linked to ECM-receptor interactions, including laminin subunit alpha 2(LAMA2). RNA immunoprecipitation (RIP) assay revealed Mex3a directly bound to LAMA2 mRNA and Mex3a increased the instability of LAMA2 mRNA in LUAD cells. Furthermore, we discovered that LAMA2 was surprisingly downregulated in LUAD and inhibited LUAD metastasis. LAMA2 knockdown partially reverse the decrease of cell migration and invasion caused by Mex3a knockdown. In addition, we found that both Mex3a and LAMA2 could influence PI3K-AKT pathway, which are downstream effectors of the ECM-receptor pathway. Moreover, the reduced activation of PI3K-AKT pathway in caused by Mex3a depletion was rescued by LAMA2 knockdown. In conclusion, we demonstrated that Mex3a downregulates LAMA2 expression to exert a prometastatic role in LUAD. Our study revealed the prognostic and prometastatic effects of Mex3a in LUAD, suggesting that Mex3a can serve as a prognostic biomarker and a target for metastatic therapy.

Highlights

Lung adenocarcinoma (LUAD) is the main malignant tumor of the lung and is one of the most common causes of cancer-related death worldwide
Similar to our microarray results, we found that the mRNA expression of Mex3a was upregulated in LUAD tissues compared to adjacent normal tissues (Fig. 1c–e)
We knockdown LAMA2 with simultaneous knockdown of Mex3a expression in H1299 and A549 cell, and discovered that knockdown of LAMA2 partially attenuated the decreased cell migration and invasion capacity caused by Mex3a knockdown (Fig. 6b, c, e, f). These results demonstrated that LAMA2 was an important inhibitory factor in LUAD metastasis and that LAMA2 was essential for inhibiting the metastasis ability of LUAD induced by Mex3a

Summary

Introduction

Lung adenocarcinoma (LUAD) is the main malignant tumor of the lung and is one of the most common causes of cancer-related death worldwide. As RNA-binding protein, Mex3a gene is one of four human homologous Mex[3] genes. The four Mex[3] proteins in humans have similar specific structures that bind RNA and are involved in the regulation of RNA metabolism[1]. Studies have shown that Mex3A is part of newly discovered processing bodies[1]. Processing bodies is an important site in the post-transcriptional regulation of mRNA and plays a crucial role in the regulation of gene expression. Studies in recent years have shown that Mex3a may be closely linked to cancer. Recent studies have reported that Mex3a is overexpressed in cancers like bladder urothelial carcinoma and Wilm’s tumor Mex3a gene is closely related to the proliferation, apoptosis, and metastasis of gastric cancer cells[4,5,6]. Little is known about the expression and function of

Methods

Results

Conclusion