Hyaluronan-CD44 interaction promotes c-Jun signaling and miRNA21 expression leading to Bcl-2 expression and chemoresistance in breast cancer cells

MicroRNA-21 (miR-21) is associated with the development of solid tumors progression including breast cancer. In this study we investigated matrix hyaluronan (HA)-CD44 (a primary HA receptor) interaction with c-Jun N-Terminal Kinase (JNK)/c-Jun signaling in MDA-MB-468 breast cancer cells [a triple-negative (estrogen receptor-negative/progesterone receptor-negative/HER2-negative) breast cancer cell line]. Our results indicated that HA binding to CD44 promotes c-Jun nuclear translocation and transcriptional activation. Further analyses revealed that miR-21 is regulated by an upstream promoter containing AP1 binding site(s), and chromatin immunoprecipitation (CHIP) assays demonstrated that stimulation of miR-21 expression by HA/CD44 interaction is c-Jun-dependent in these breast cancer cells. This process results in an increase of the anti-apoptosis protein Bcl-2 and upregulation of inhibitors of the apoptosis family of proteins (IAPs) as well as chemoresistance in MDA-MB-468 cells. Treatment with c-Jun specific small interfering RNAs effectively blocks HA-mediated c-Jun signaling and abrogates miR-21 production as well as causes downregulation of survival proteins (Bcl-2 and IAPs) and enhancement of chemosensitivity. In addition, our results demonstrated that anti-miR-21 inhibitor not only downregulates Bcl-2/IAP expression but also increases chemosensitivity in HA-treated breast cancer cells. Together, these findings suggest that the HA/CD44-induced c-Jun signaling plays a pivotal role in miR-21 production leading to survival protein (Bcl-2/IAP) upregulation and chemoresistance in triple negative breast cancer cells such as MDA-MB-468 cell line. This novel HA/CD44-mediated c-Jun signaling pathway and miR-21 production provide a new drug target for the future intervention strategies to treat breast cancer.