Genetic Variation in MicroRNA-423 Promotes Proliferation, Migration, Invasion, and Chemoresistance in Breast Cancer Cells.

Sebastian Morales-Pison,Cristian Gutiérrez-Vera,Héctor R Contreras,José Miguel Reyes,Valentina Carrasco,Lilian Jara,Patricio Gonzalez-Hormazabal,Julio C Tapia,Leandro J Carreño

doi:10.3390/ijms23010380

Abstract

MicroRNA-423 (miR-423) is highly expressed in breast cancer (BC). Previously, our group showed that the SNP rs6505162:C>A located in the pre-miR-423 was significantly associated with increased familial BC risk in patients with a strong family history of BC. Therefore, in this study, we evaluated the functional role of rs6505162 in mammary tumorigenesis in vitro to corroborate the association of this SNP with BC risk. We found that rs6505162:C>A upregulated expression of both mature miR-423 sequences (3p and 5p). Moreover, pre-miR-423-A enhanced proliferation, and promoted cisplatin resistance in BC cell lines. We also showed that pre-miR-423-A expression decreased cisplatin-induced apoptosis, and increased BC cell migration and invasion. We propose that the rs6505162-A allele promotes miR-423 overexpression, and that the rs6505162-A allele induces BC cell proliferation, viability, chemoresistance, migration, and invasion, and decreases cell apoptosis as a consequence. We suggest that rs6505162:C>A is a functional SNP site with potential utility as a marker for early diagnosis, prognosis, and treatment efficacy monitoring in BRCA1/2-negative BC patients, as well as a possible therapeutic target.

Highlights

Breast cancer (BC) is the most frequent cancer affecting women worldwide
In gastric cancers [15,16,17,18], glioblastomas [19,20,21,22], laryngeal carcinomas [14], lung cancers [23,24,25], and endometrial cancers [26,27], miR-423 is implicated in cell proliferation, migration, and invasion. miR-423 seems to influence proliferation and apoptosis in colorectal [28,29,30,31] and prostate cancers [32]
MiR-423-3p and miR-423-5p levels were significantly increased in both MCF-7 and MDA-MB-231 BC cells transfected with pre-miR-423-A versus pre-miR-423-C (Figure 1B,C). These results suggest that the expression levels of both mature miR-423 sequences (3p and 5p) are upregulated in BC cells by the presence of the rs6505162-A allele in pre-miR-423

Summary

Introduction

Breast cancer (BC) is the most frequent cancer affecting women worldwide. In Chile, BC has the highest mortality rate among cancers in women (16.6/100,000 women) [1]. Evidence has emerged to support a role of microRNAs (miRNAs) in BC development and progression [3,4]. These molecules can regulate gene expression by degrading or blocking translation of their specific target mRNAs, mainly by binding to their 3 -unstranslated region (UTR) [5,6]. Growing evidence indicates that miRNA variations and mutations are correlated with various human cancers, including BC [9,10,11]. MiR-423 promotes cell growth, and regulates G(1)/S transition by targeting p21 Cip1/waf1 [13]. In gastric cancers [15,16,17,18], glioblastomas [19,20,21,22], laryngeal carcinomas [14], lung cancers [23,24,25], and endometrial cancers [26,27], miR-423 is implicated in cell proliferation, migration, and invasion. miR-423 seems to influence proliferation and apoptosis in colorectal [28,29,30,31] and prostate cancers [32]

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