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

Liqun Chen,Lilly Y W Bourguignon

doi:10.1186/1476-4598-13-52

Abstract

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.

Highlights

Matrix Hyaluronan (HA) is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues [1]
HA-CD44 interaction activates Jun N-Terminal Kinase (JNK) and c-Jun signaling in breast tumor cells Previous studies [1,25,30,31,32,33] indicated that HA/CD44mediated oncogenic signaling plays an important role in the development of several solid tumors including breast cancer
In this study we focused on the question of whether HA can regulate JNK activation and c-Jun signaling in breast tumor cells

Summary

Introduction

Matrix Hyaluronan (HA) is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues [1]. RHAMM whose cell surface form is designated as CD168, was found in breast cancer cells [8,9] Both CD44 and RHAMM mediate hyaluronan signaling [10]. Since CD44 was identified as the first integral HA binding “receptor”, HAmediated CD44 signaling has received a great deal of attention in cancer field Both CD44 and HA are overexpressed/elevated at sites of tumor attachment [1,4]. HA binding to CD44 affects cell adhesion to extracellular matrix (ECM) components, and stimulates a variety of tumor cell-specific functions leading to breast cancer progression [2,3,11,12,13,14]. The oncogenic mechanism(s) occurring during HA-activated and CD44-specific breast cancer progression remain(s) to be determined

Methods

Results

Conclusion