EMMPRIN Down-regulating miR-106a/b Modifies Breast Cancer Stem-like Cell Properties via Interaction with Fibroblasts Through STAT3 and HIF-1α.

Yonglei Liu,Jingling Zhang,Xiangjun Sun,Meilin Li

doi:10.1038/srep28329

Abstract

Extracellular matrix metalloproteinase inducer (EMMPRIN) is a heavily glycosylated protein and expresses in cancer cells widely, which plays important roles in tumor progression. However, the role of EMMPRIN in breast cancer stem-like cell properties by interaction with fibroblasts is not known. In the present study, we investigated the effects of fibroblasts on breast cancer stem-like cells. We found that fibroblasts activated by co-cultured breast cancer cells produced higher levels of EMMPRIN, which stimulated the stem-like cell specific, self-renewal and sphere-forming phenotype in breast cancer cells. Increased EMMPRIN expression in activated fibroblasts increased the expression of STAT3 and HIF-1α and showed cancer stem-like cell features in breast cancer cells. We also found that EMMPRIN could down-regulate miR-106a and miR-106b expression in breast cancer cells, which led to activating STAT3 and enhancing HIF-1α expression. Our results illustrated that EMMPRIN has an important role in breast cancer stem-like cells by activation STAT3/HIF-1α through interaction with cancer cells and fibroblasts. The study for the first time indicated that cancer cells and fibroblasts interaction promotes breast cancer cells showing stem-like cells through up-regulation EMMPRIN, and led to inhibiting miR-106a/b expression which targets both STAT3 and HIF-1α expression.

Highlights

Cancer stem cells (CSC) play important roles in tumor initiation, progression and therapeutic response[1]
The data showed that soluble Extracellular matrix metalloproteinase inducer (EMMPRIN) increased in conditioned medium (CM) from co-cultured breast cancer cells and Hs578Bst cells compared with CM from only Hs578Bst cells or CM from co-cultured MCF10A and Hs578Bst cells (Fig. 1A)
We chosed BT474 and SUM102 to verify the above result, when the cells were treated with CM, total EMMPRIN protein levels in breast cancer cells were enhanced in the two cell lines with CM from co-cultured cancer cells with Hs578Bst fibroblasts (Fig. 1C)

Summary

Introduction

Cancer stem cells (CSC) play important roles in tumor initiation, progression and therapeutic response[1]. Fibroblasts are the most enriched cells in tumor stroma and play important roles in cancer progression including metastasis, proliferation, anti-apoptosis, angiogenesis and chemoresistance by interaction with cancer cells[4,5,6]. Previous studies suggest that EMMPRIN could promote cancer progression by interaction with fibroblasts in tumor stroma[18]. It is still unknown whether EMMPRIN could induce breast cancer cell exhibiting stem-like cells and its molecular mechanism. That EMMPRIN could down-regulate miR-106a/b which targets STAT3-HIF-1αto promote breast cancer cells showing stem-like cells and may play a fundamental role in regulation of CSC

Methods

Results

Conclusion