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

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.

Oncogenic Potential of the Dual-Function Protein MEX3A

“…However, in vitro and mouse xenograft analyses support a potential function of MEX3A in mesenchymal transition. Consistently, MEX3A knockdown studies revealed migratory potential by reducing CDH2, VIM, SNAI1/2 and increasing CDH1 protein levels, and additionally exhibited reduced lung metastasis [ 75 ]. This could be facilitated by an altered PTEN function due to K27-linked ubiquitination mediated by MEX3A, as proposed for MEX3C [ 26 ], but further mechanistic studies are necessary to exclude a transcriptional or post-transcriptional regulation of EMT processes.…”

“…This could be facilitated by an altered PTEN function due to K27-linked ubiquitination mediated by MEX3A, as proposed for MEX3C [ 26 ], but further mechanistic studies are necessary to exclude a transcriptional or post-transcriptional regulation of EMT processes. Along this line, several reports indicate a role of MEX3A in the activation of the PIK3CA/AKT signaling pathway [ 67 , 74 , 75 , 82 ] that is involved in the regulation of, e.g., proliferation, metabolism, transcriptional control or cell migration (for review see [ 83 ]). Accordingly, MEX3A induced migratory phenotypes, as well as pronounced mesenchymal expression patterns, could be mediated by the activation of the AKT pathway affecting inter alia SNAI1, SNAI2 and TWIST levels [ 84 ], which are the main transcriptional drivers of EMT.…”

Identification of The Potential Signature Genes Between Lung Adenocarcinoma and Lung Squamous Cell Carcinoma

“…The KEGG pathway analysis was enriched by the DEmiRNA and DEmRNA. Phagosome, Human T-cell leukemia virus 1 infection, and ECM-receptor interaction were significantly enriched in the AD, which was closely associated with the immune microenvironment and the maintenance of cell structure and function [24,25]. The cell cycle and p53 signaling pathways were significantly enriched in the SC, which was closely connected to the basic biological processes and signaling pathways.…”

Oncogenic role of abnormal spindle‑like microcephaly‑associated protein in lung adenocarcinoma

“…Total RNA was isolated from cell lines and tissues using the RNeasy Mini kit (Qiagen GmbH). Related data were uploaded in the Gene Expression Omnibus (GEO) ( http://www.ncbi.nlm.nih.gov/geo ) dataset GSE140797 ( 19 ). The gene expression levels and clinical data of patients with LUAD from The Cancer Genome Atlas (TCGA) were downloaded from UCSC Xena Browser ( https://xenabrowser.net/ ).…”