Adipose derived stem cells promote tumor metastasis in breast Cancer cells by stem cell factor inhibition of miR20b.

ABSTRACT

Breast cancer (BC) metastasis after surgery is associated with the tumor microenvironment and especially with adipose tissue-derived mesenchymal stem cells (ASCs) that have been shown to promote the BC progression. To better understand the role of ASCs in tumor metastasis, our study explored a novel mechanism that mediates the negative regulation of miR20b during ASC-induced tumor metastasis of BC cells. In this study, we found that the migration and invasion abilities of BC cells are markedly increased coculture with ASCs. By studying the regulatory mechanism, we found that miR20b biogenesis in BC cells can be attenuated by ASC-released stem cell factor (SCF) through the downstream c-Kit/MAPK-p38/E2F1 signaling cascade and that miR-20b acts as a tumor suppressor miRNA in the inhibition of BC migration and invasion. HIF-1α and VEGFA are the target genes of miR20b and miR20b downregulation activated HIF-1α-mediated VEGFA transcription and ASC-induced BC migration and invasion. The upregulation of miR20b abrogated the activation of EMT and lung metastasis of breast cancer cells cocultured with ASCs by the inhibition of N-cadherin, vimentin and Twist expression in vitro and in vivo. Collectively, our findings indicate that downregulation of miR20b by ASCs/SCF activates HIF-1α/VEGFA and induces BC cell EMT and metastasis, suggesting that this process is activated by the p-c-Kit/MAPK-p38/E2F1 pathway.