miR-221/222 promote cancer stem-like cell properties and tumor growth of breast cancer via targeting PTEN and sustained Akt/NF-κB/COX-2 activation

Abstract

MicroRNAs (miRNAs) play an important role in regulating cancer stem cell (CSC). Previous studies have shown that microRNA-221/222 (miR-221/222) cluster are involved in the propagation of breast cancer stem cell (BCSC), however, the underlying molecular mechanisms are still not fully understood. In this study, we found that miR-221/222 were overexpressed in highly aggressive breast cancer MDA-MB-231 cells, that are enriched in markers for epithelial-mesenchymal transition (EMT) and BCSCs, than in MCF-7 cells. Phosphatase and tensin homolog (PTEN) was confirmed to be the target of miR-221/222 in breast cancer cells. MiR-221/222 enhanced breast cancer cell growth, migration and invasion by downregulating PTEN. Importantly, both ectopic expression of miR-221/222 and PTEN knockdown increased the mammosphere formation capacity and the expression of the stemness marker ALDH1. MiR-221/222 lentivirus vector infected MCF-7 cells produced larger subcutaneous tumors, while shRNA vector of PTEN showed similar trend. Along with the downregulation of PTEN caused by miR-221/222 in the breast cancer cells and the xenograft tumor tissues, Akt phosphorylation (p-Akt), NF-κB p65 and phosphorylated p65 (p-p65), and cyclooxygenase-2 (COX-2) were all overexpressed compared to the negative control. Taken together, our findings indicate that miR-221/222 play a critical role in the propagation of BCSCs and tumor growth possibly through targeting PTEN, which in turn activating the Akt/NF-κB/COX-2 pathway. MiR-221/222 might represent the potential target of breast cancer therapy.

Keywords: Breast cancer; Cancer stem cell; Cyclooxygenase-2; MicroRNA-221/222; NF-κB; PTEN/Akt pathway.