Zhang Weijie, Qian Pengxu, Zhang Xiao, Zhang Min, Wang Hong, Wu Mingming, Kong Xiangjun, Tan Sheng, Ding Keshuo, Perry Jo K, Wu Zhengsheng, Cao Yuan, Lobie Peter E, Zhu Tao
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.
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.
J Biol Chem. 2015 May 29;290(22):13812-29. doi: 10.1074/jbc.M115.653261. Epub 2015 Apr 14.
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.
人生长激素（hGH）在青春期乳腺生长、发育及性成熟过程中发挥着关键作用。大量研究报道，自分泌/旁分泌hGH是一种原位表达的癌蛋白，可促进正常乳腺上皮细胞发生致癌转化。据报道，自分泌/旁分泌hGH还能促进乳腺上皮细胞的上皮-间质转化（EMT）及侵袭。然而，其潜在机制在很大程度上仍不清楚。据报道，微小RNA（miRNA）参与癌症多种细胞功能的调控。为了确定自分泌/旁分泌hGH是否通过调节miRNA表达促进EMT和侵袭，我们使用稳定表达野生型或翻译缺陷型hGH基因的MCF-7细胞进行了微阵列分析，并确定miR-96-182-183为自分泌/旁分泌hGH调节的miRNA簇。miR-96-182-183的强制表达赋予上皮样MCF-7细胞间充质表型，并在体外促进侵袭行为，在体内促进播散。此外，我们观察到miR-96-182-183通过直接并同时抑制BRMS1L（乳腺癌转移抑制因子1样）基因表达来促进EMT和侵袭。miR-96和miR-182还靶向生长激素受体（GHR），在hGH-GHR信号通路中提供了一个潜在的负反馈环。我们进一步证明，自分泌/旁分泌hGH通过信号转导和转录激活因子3（STAT3）和信号转导和转录激活因子5（STAT5）信号刺激miR-96-182-183表达，并促进EMT和侵袭。与转移性乳腺癌组织中自分泌/旁分泌hGH表达升高一致，miR-96-182-183表达也显著增强。因此，我们阐述了miRNA-96-182-183簇的作用，并阐明了一条新的hGH-GHR-STAT3/STAT5-miR-96-182-183-BRMS1L-ZEB1/E47-EMT/侵袭轴，这为进一步了解自分泌/旁分泌hGH刺激乳腺癌EMT和侵袭的机制提供了依据。
