title: Autocrine/Paracrine Human Growth Hormone-stimulated MicroRNA 96-182-183 Cluster Promotes Epithelial-Mesenchymal Transition and Invasion in Breast Cancer.
abstract: Human growth hormone (hGH) plays critical roles in pubertal mammary gland growth, development, and sexual maturation. Accumulated studies have reported that autocrine/paracrine hGH is an orthotopically expressed oncoprotein that promotes normal mammary epithelial cell oncogenic transformation. Autocrine/paracrine hGH has also been reported to promote mammary epithelial cell epithelial-mesenchymal transition (EMT) and invasion. However, the underlying mechanism remains largely obscure. MicroRNAs (miRNAs) are reported to be involved in regulation of multiple cellular functions of cancer. To determine whether autocrine/paracrine hGH promotes EMT and invasion through modulation of miRNA expression, we performed microarray profiling using MCF-7 cells stably expressing wild type or a translation-deficient hGH gene and identified miR-96-182-183 as an autocrine/paracrine hGH-regulated miRNA cluster. Forced expression of miR-96-182-183 conferred on epithelioid MCF-7 cells a mesenchymal phenotype and promoted invasive behavior in vitro and dissemination in vivo. Moreover, we observed that miR-96-182-183 promoted EMT and invasion by directly and simultaneously suppressing BRMS1L (breast cancer metastasis suppressor 1-like) gene expression. miR-96 and miR-182 also targeted GHR, providing a potential negative feedback loop in the hGH-GHR signaling pathway. We further demonstrated that autocrine/paracrine hGH stimulated miR-96-182-183 expression and facilitated EMT and invasion via STAT3 and STAT5 signaling. Consistent with elevated expression of autocrine/paracrine hGH in metastatic breast cancer tissue, miR-96-182-183 expression was also remarkably enhanced. Hence, we delineate the roles of the miRNA-96-182-183 cluster and elucidate a novel hGH-GHR-STAT3/STAT5-miR-96-182-183-BRMS1L-ZEB1/E47-EMT/invasion axis, which provides further understanding of the mechanism of autocrine/paracrine hGH-stimulated EMT and invasion in breast cancer.
authors: From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China, the Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors: Weijie
authors: W
authors: Zhang
authors: From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Pengxu
authors: P
authors: Qian
authors: From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Xiao
authors: X
authors: Zhang
authors: From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China, the Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
authors: Min
authors: M
authors: Zhang
authors: From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Hong
authors: H
authors: Wang
authors: From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Mingming
authors: M
authors: Wu
authors: From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Xiangjun
authors: X
authors: Kong
authors: From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Sheng
authors: S
authors: Tan
authors: From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Keshuo
authors: K
authors: Ding
authors: the Liggins Institute and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1023, New Zealand.
authors: Jo K
authors: JK
authors: Perry
authors: From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China, the Department of Pathology, Anhui Medical University, Hefei, Anhui 230027, China, and.
authors: Zhengsheng
authors: Z
authors: Wu
authors: the Department of Pathology, Anhui Medical University, Hefei, Anhui 230027, China, and.
authors: Yuan
authors: Y
authors: Cao
authors: the Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 117599, Singapore csipel@nus.edu.sg.
authors: Peter E
authors: PE
authors: Lobie
authors: From the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China, the Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China, zhut@ustc.edu.cn.
authors: Tao
authors: T
authors: Zhu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000166:cytology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D005810:Multigene Family; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: C410024:BRMS1 protein, human; C533449:MIRN183 microRNA, human; C541492:MIRN96 microRNA, human; D035683:MicroRNAs; C538984:Mirn182 microRNA, human; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D019382:Human Growth Hormone
keywords: BRMS1L; breast cancer; epithelial-mesenchymal transition (EMT); growth hormone; invasion; miR-96-182-183 cluster; microRNA (miRNA)