MicroRNA-488 inhibits progression of colorectal cancer via inhibition of the mitogen-activated protein kinase pathway by targeting claudin-2

Abstract

Colorectal cancer (CRC) affects people globally and lymph node metastasis (LNM) is an important indicator of poor clinical outcome in CRC. The current study aims to evaluate the role of microRNA-448 (miR-488) and claudin-2 (CLDN2) in epithelial-mesenchymal transition (EMT) and LNM of CRC through the MAPK signaling pathway. Firstly, microarray analysis indicated that MiR-488 was poorly expressed in CRC, whereas CLDN2 was highly expressed. Additionally, the bioinformatics website MicroRNA.org, and the dual luciferase reporter gene assay found that CLDN2 was a target gene of miR-488. Next, the results for the correlations between expression of miR-488 and clinicopathological characteristics of CRC indicated that the expression of miR-488 was closely associated with differentiation degree, LNM, and Dukes stages in CRC patients. Moreover, over-expression of miR-488 inhibited the activation of the MAPK signal transduction pathway. Notably, loss- and gain- of-function experiments demonstrated that up-regulation of miR-488 suppressed SW480 cell viability, invasion, and migration, and promoted apoptosis in SW480 cells. Finally, over-expression of miR-488 inhibited LNM, MLVD, and tumor growth in nude mice. We conclude that over-expression of miR-488 could suppress the cell proliferation, EMT, and LNM of CRC cells via inhibition of CLDN2-mediated MAPK signaling pathway, which could be a new molecular therapy target for CRC.

MicroRNAs associated with lung squamous cell carcinoma: New prognostic biomarkers and therapeutic targets

“…27,28 miR-383 is an inhibitor of lung cancer, which can target the 3′UTR of endothelial PAS domain protein 1 mRNA, which is significantly associated with poor prognosis in patients. 29,30 Expression of miR-448 has been linked to the molecular mechanisms of various tumors, such as LUSC, 31 osteosarcoma, 32 pancreatic ductal adenocarcinoma, 33 colorectal cancer, 34 breast cancer, 35,36 and others. Among these many studies, one report has shown that miR-448 expression is associated with TNM staging of LUSC.…”

Claudin-2: Roles beyond Permeability Functions

“…Finally, several miRNAs, including miR-488, miR-16, and the miR-199a-5p/214-3p gene cluster were also implicated in claudin-2 control [54,77,78]. For example, the miR-199a-5p/214-3p gene cluster was found to be downstream from serum response factor (SRF), a pro-fibrotic transcription factor, and was implicated in high glucose-induced claudin-2 downregulation in peritoneal mesothelial cells undergoing epithelial-mesenchymal transition (EMT) [78].…”

“…In A549 lung adenocarcinoma cells, ephrinA1 reduced both claudin-2 expression and proliferation, and both were mediated by Cdx-2 [115]. Recently, miR-488 was shown to suppress both claudin-2 expression and cell viability in colorectal carcinoma cells [77].…”

“…Another study suggested that in osteosarcoma cells claudin-2 loss augmented migration via the afadin/ERK pathway [130]. Along the same lines miR-488 was shown to regulate invasion and lymph node metastasis in colon cancer cells through claudin-2-dependent control of the MAPK pathway [77].…”

An in silico approach to identify and prioritize miRNAs target sites polymorphisms in colorectal cancer and obesity

“…In this case, the miR-30 family, miR-504, miR-34c, miR-488, miR-15b, miR-195, miR-497, miR-15a, miR-503, miR-141, miR-182, miR-96, and miR-136 were also related to invasion, proliferation, metastasis and tumor growth, or survival of several cancers including CRC. [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] However, there are few studies on the role of included prioritized miRNAs for interactions with obesity. For obesity there are some studies on mice, for instance, miR-16-5p decrease with high weight and a mutation in miR-16 gene lead to increasing in body weight.…”