Autocrine hGH stimulated miRNA 96‐182‐183 cluster promotes epithelial‐mesenchymal transition and invasion in breast cancer (LB201)

Abstract

Human growth hormone (hGH) plays critical roles in pubertal mammary gland growth, development and sexual maturation. Accumulated studies reported that autocrine hGH is an orthotopically expressed oncogene and could induce normal mammary epithelial cell malignant transformation. Previously, our group reported autocrine hGH promotes mammary epithelial cell epithelial‐mesenchymal transition (EMT), facilitating invasion and increasing MMP activity. However, how hGH regulates EMT and invasion remains largely obscure. miRNAs are widely reported to involve in multiple processes of cancer. To determine whether autocrine hGH promotes EMT through miRNAs, we performed microarray profiling using MCF‐7 cells stably expressing normal or translation deficient hGH. We found that miR‐96‐182‐183 cluster exhibited highest response to autocrine hGH stimulation. We further observed that forced expression of miR‐96‐182‐183 conferred epithelial MCF‐7 cells with mesenchymal phenotype and invasive behaviors both in vitro and in vivo. Moreover, we revealed that miR‐96‐182‐183 promotes EMT and invasion by directly and simultaneously suppressing Breast Cancer Metastasis Suppressor 1‐like (BRMS1L) gene. In addition, miR‐96 and miR‐182 target GHR, introducing a potential negative feedback loop in the hGH‐GHR signaling pathway. Mechanically, we found that autocrine hGH stimulates miR‐96‐182‐183 expression and facilitates EMT and invasion via STAT3 and STAT5 signaling pathway. Clinically, we inspected that miR‐96‐182‐183 expression is remarkably enhanced in metastatic breast tumors. Together, we elucidate one novel hGH‐GHR‐STAT3/STAT5‐miR‐96‐182‐183 cluster‐BRMS1L‐ZEB1/E47‐EMT‐invasion axis, which sheds new insights into understanding the mechanism of autocrine hGH stimulated EMT and invasion of breast cancer cells.