A miR-200b/200c/429-Binding Site Polymorphism in the 3′ Untranslated Region of the AP-2α Gene Is Associated with Cisplatin Resistance

Abstract

The transcription factor AP-2α functions as a tumor suppressor by regulating various genes that are involved in cell proliferation and apoptosis. Chemotherapeutic drugs including cisplatin induce post-transcriptionally endogenous AP-2α, which contributes to chemosensitivity by enhancing therapy-induced apoptosis. microRNAs (miRNAs) miR-200b, miR-200c and miR-429 (miR-200b/200c/429) are up-regulated in endometrial and esophageal cancers, and their overexpression correlates with resistance to cisplatin treatment. Using computational programs, we predicted that the 3′ untranslated region (UTR) of AP-2α gene contains a potential miRNA response element (MRE) for the miR-200b/200c/429 family, and the single nucleotide polymorphism (SNP) site rs1045385 (A or C allele) resided within the predicted MRE. Luciferase assays and Western blot analysis demonstrated that the miR-200b/200c/429 family recognized the MRE in the 3′ UTR of AP-2α gene and negatively regulated the expression of endogenous AP-2α proteins. SNP rs1045385 A>C variation enhanced AP-2α expression by disrupting the binding of the miR-200b/200c/429 family to the 3′ UTR of AP-2α. The effects of the two polymorphic variants on cisplatin sensitivity were determined by clonogenic assay. The overexpression of AP-2α with mutant 3′ UTR (C allele) in the endometrial cancer cell line HEC-1A, which has high levels of endogenous miR-200b/200c/429 and low levels of AP-2α protein, significantly increased cisplatin sensitivity, but overexpression of A allele of AP-2α has no significant effects, compared with mock transfection. We concluded that miR-200b/200c/429 induced cisplatin resistance by repressing AP-2α expression in endometrial cancer cells. The SNP (rs1045385) A>C variation decreased the binding of miR-200b/200c/429 to the 3′ UTR of AP-2α, which upregulated AP-2α protein expression and increased cisplatin sensitivity. Our results suggest that SNP (rs1045385) may be a potential prognostic marker for cisplatin treatment.

MicroRNA-203 induces apoptosis by upregulating Puma expression in colon and lung cancer cells

“…Surprisingly, miRNAs also have the potential to suppress several target genes simultaneously (2). Similarly, numerous miRNAs play important roles as either oncogenes or tumor suppressor genes, and are involved in a variety of cellular processes including proliferation, apoptosis, tumorigenesis, and chemoresistance (3)(4)(5). Furthermore, several studies have shown that dysregulated miRNA expression is frequently found in various human cancers (6)(7)(8)(9).…”

Inferring Single Nucleotide Polymorphisms in MicroRNA Binding Sites of Lung Cancer-related Inflammatory Genes

“…Some researchers (Richardson et al, 2011) basing on the list of SNPs from GWAS, or in strong LD with a GWAS SNP performed a genome-wide scan of SNPs that abrogate or create miRNA recognition element (MRE) seed sites (MRESS) and identified high priority candidate SNPs for functional studies and for disease risk prediction. Other researchers (Wu et al, 2011) discovered the relationship between specific genes expression or miRNA level and diseases, so they thought that SNPs within miRNA target sites may influence their encoded target-mRNAs and their downstream effectors and they would predict the 3'UTR of these genes contains potential MREs and verify that these mutations maybe as a key in regulating gene expression. At present, all studies the on gene variation in miRNA-binding regions were performing several kinds of arithmetic or getting help from various websites.…”

MicroRNAs in endometrial cancer

“…Expression of miR-200b, miR-200c and miR-429, which inhibit transcription factor AP-2α, is upregulated in endometrial cancer and the rate of expression is positively correlated with resistance to cisplatin. However, SNP (rs1045385A>C) decreases the effect on AP-2α, and sensitivity to cisplatin is increased (Wu et al, 2011). These studies suggest that a comprehensive investigation of which miRNA causes resistance or increases sensitivity to a particular drug will improve selection of drug treatment.…”