MiR-23a promotes TGF-β1-induced EMT and tumor metastasis in breast cancer cells by directly targeting CDH1 and activating Wnt/β-catenin signaling.

Wei Li,Haining Yu,Yanlv Ren,Da Pang,Chunxiao Liu,Cheng Qian,Wenjie Li,Fei Ma,Zhigao Li,Bo Lei

doi:10.18632/oncotarget.18422

Abstract

TGF-β1-induced epithelial-mesenchymal transition (EMT) has been proved to be associated with metastasis of breast cancer cells. We attempted to detect a novel mechanism that microRNAs mediated the TGF-β1-induced EMT in the process of breast cancer metastasis. Here we reported that the expression of miR-23a was higher in breast cancer cells with high metastasis ability and patients with lymph node metastasis and the treatment of TGF-β1 significantly upregulated the expression of miR-23a in breast cancer cells. We found that miR-23a was upregulated by TGF-β1 post-transcriptionally and Smads directly bound the RNA Smad binding element (R-SBE) of miR-23a. Functional studies showed that inhibition of miR-23a suppressed the TGF-β1-induced EMT, migration, invasion and metastasis of breast cancer both in vitro and in vivo. In addition, we determined that miR-23a directly targeted and suppressed CDH1, one important gene in EMT phenomenon. Notably, Wnt/β-catenin signaling was activated by the suppression of CDH1 in the miR-23a mediated process of TGF-β1-induced EMT and tumor invasion. These results demonstrate that miR-23a promotes TGF-β1-induced tumor metastasis in breast cancer by targeting CDH1 and activating Wnt/β-catenin signaling. Taken together, our results indicate a novel regulatory mechanism of TGF-β1-induced EMT and suggest that miR-23a might be a potential target in breast cancer therapy.

Highlights

At present, tumor metastasis is the leading cause of breast cancer death among women because of its surgically inoperable nature and the resistance to existing therapeutic drugs [1, 2]
MiR-23a expression was higher in patients with lymph node metastasis and metastatic cell lines and the treatment of TGF-β1 upregulated the expression of miR-23a in MCF-7 and MDAMB-231 cell lines
A previous study showed that activation of TGF-β receptor type I led to phosphorylation of receptor-specific SMAD (R-SMAD) proteins and R-SMADs could play a role in the post-transcriptional regulation of microRNAs [16]

Summary

Introduction

Tumor metastasis is the leading cause of breast cancer death among women because of its surgically inoperable nature and the resistance to existing therapeutic drugs [1, 2]. Recent studies revealed that epithelialmesenchymal transition (EMT) played a pivotal role in the process of breast cancer metastasis. During the EMT process, tumor cells lose cell polarity [5] and the connection between cells becomes loose [6]. This process of EMT is the crucial step for cancer cells to metastasis. TGF-β, a cytokine with multiple biological functions, was first described as an inducer of EMT in normal mammary epithelial cells, and several subsequent studies reported important roles of TGF-β-induced EMT in tumor metastasis [7]. It was reported that TGF-β activated the www.impactjournals.com/oncotarget

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Results

Conclusion