ErbB2-intronic microRNA-4728: a novel tumor suppressor and antagonist of oncogenic MAPK signaling.

D C Schmitt,S Mcclellan,W Zhang,E-Ye Ahn,L Madeira Da Silva,A M Schuler,J F Andrews,S Lim,M Tan,Z Liu,A G Kahn,M Zhou,R Arora

doi:10.1038/cddis.2015.116

Abstract

Although the role of the ErbB2/HER2 oncogene in cancers has been extensively studied, how ErbB2 is regulated remains poorly understood. A novel microRNA, mir-4728, was recently found within an intron of the ErbB2 gene. However, the function and clinical relevance of this intronic miRNA are completely unknown. Here, we demonstrate that mir-4728 is a negative regulator of MAPK signaling through directly targeting the ERK upstream kinase MST4 and exerts numerous tumor-suppressive properties in vitro and in animal models. Importantly, our patient sample study shows that mir-4728 was under-expressed in breast tumors compared with normal tissue, and loss of mir-4728 correlated with worse overall patient survival. These results strongly suggest that mir-4728 is a tumor-suppressive miRNA that controls MAPK signaling through targeting MST4, revealing mir-4728's significance as a potential prognostic factor and target for therapeutic intervention in cancer. Moreover, this study represents a conceptual advance by providing strong evidence that a tumor-suppressive miRNA can antagonize the canonical signaling of its host oncogene.

Highlights

The human epidermal growth factor receptor 2 gene (ErbB2/HER2, hereafter called ErbB2), encodes a 185-kDa transmembrane protein that belongs to the epidermal growth factor receptor family.[3,4] Through its downstream signaling pathways, such as the mitogen-activated protein kinase (MAPK) pathway, ErbB2 regulates several important cell functions in cancer development and progression, such as growth, differentiation, and apoptosis.[5]
These findings indicate that mir-4728 decreases the growth and metastatic potential of breast cancer cells, and mir-4728 may sensitize breast cancer cells to Taxol treatment
As previous reports have shown that some intronic miRNAs can directly target their host,[9,10] we studied whether mir-4728 could function as a negative feedback mechanism by directly targeting its host gene, ErbB2

Summary

Introduction

The human epidermal growth factor receptor 2 gene (ErbB2/HER2, hereafter called ErbB2), encodes a 185-kDa transmembrane protein that belongs to the epidermal growth factor receptor family.[3,4] Through its downstream signaling pathways, such as the mitogen-activated protein kinase (MAPK) pathway, ErbB2 regulates several important cell functions in cancer development and progression, such as growth, differentiation, and apoptosis.[5] The ErbB2 gene is amplified or overexpressed in approximately 25% of human breast carcinomas and plays a role in many other human malignancies.[6,7]. The mechanisms by which intronic miRNAs regulate oncogenes or tumor-suppressor genes and the roles of intronic miRNAs in cancer development and progression are poorly understood. We demonstrated a critical role of mir-4728 in the regulation of MAPK signaling and breast cancer tumorigenesis. Genes and Genomes; MAPK, Mitogen-activated protein kinase; miRNA, MicroRNA; MST4, Mammalian STE20-like protein kinase 4; OCR, Oxygen consumption rate; PBS, Phosphate buffered saline; PR, Progesterone receptor; qPCR, Real-time quantitative PCR; S.E.M., Standard error of the mean; siRNA, Small interfering RNA; STE20, Sterile 20; UTR, Untranslated region

Methods

Results

Conclusion