音猬因子-GLI家族锌指蛋白1信号通路通过调控真核翻译起始因子5A2的转录促进胰腺癌细胞的生长和迁移。
Sonic Hedgehog-GLI Family Zinc Finger 1 Signaling Pathway Promotes the Growth and Migration of Pancreatic Cancer Cells by Regulating the Transcription of Eukaryotic Translation Initiation Factor 5A2.
作者信息
Xu Xuanfu, Liu Hua, Zhang Hui, Dai Weiqi, Guo Chuanyong, Xie Chuangao, Wei Shumei, He Shengli, Xu Xiaorong
机构信息
From the *Department of Gastroenterology, The Tenth People's Hospital of Shanghai, Tongji University, Shanghai; Departments of †Pathology and ‡Gastroenterology, The Second Hospital of Zhejiang University, Hangzhou, Zhejiang Province; and §Department of Hepato-Biliary and Pancreatic Oncology, Fudan University Shanghai Cancer Center, Minhang Branch, Shanghai, China.
出版信息
Pancreas. 2015 Nov;44(8):1252-8. doi: 10.1097/MPA.0000000000000532.
OBJECTIVES
The Hh (hedgehog) signaling pathway is still waiting for further studies because its downstream molecular mechanism remains elusive. Because EIF5A2 (eukaryotic translation initiation factor 5A2) gene was up-regulated upon Gli1 (GLI family zinc finger 1) in pancreatic cancer (PC) cells, we speculated that this pathway might promote tumor progression through regulating EIF5A2.
METHODS
We investigated regulation effect of Hh signaling pathway to EIF5A2 gene transcription by Gli1 knockdown or overexpression in PC cell lines first. Then, the regulation mechanism of Gli1 to EIF5A2 gene was studied at transcription level. Finally, we studied cancer-promoting effects of Gli1-dependent EIF5A2 in PC cells.
RESULTS
The data showed that Gli1 up-regulated expression of EIF5A2 by promoting transcription via cis-acting elements in PC cells. Moreover, vimentin gene was up-regulated significantly by sonic hedgehog (SHh)/Gli1 expression increasing, and E-cadherin was significantly reduced. The EIF5A2 knockdown partially reversed cell proliferation and migration induced by artificial SHh overexpression and inhibited epithelial mesenchymal transition process in PC cells with SHh overexpression (P < 0.05).
CONCLUSIONS
Our data establish a novel transcription mechanism of Gli1 to EIF5A2 gene in cis-regulatory manner in PC cells. Thus, EIF5A2 oncogene effect could be incorporated into cancer-promoting molecular network upon Hh signaling pathway.
目的
Hh（刺猬）信号通路仍有待进一步研究，因为其下游分子机制尚不清楚。由于在胰腺癌细胞中Gli1（GLI家族锌指蛋白1）上调了EIF5A2（真核翻译起始因子5A2）基因，我们推测该通路可能通过调节EIF5A2促进肿瘤进展。
方法
我们首先通过在胰腺癌细胞系中敲低或过表达Gli1来研究Hh信号通路对EIF5A2基因转录的调节作用。然后，在转录水平研究Gli1对EIF5A2基因的调控机制。最后，我们研究了Gli1依赖的EIF5A2在胰腺癌细胞中的促癌作用。
结果
数据显示，Gli1通过促进胰腺癌细胞中顺式作用元件的转录上调EIF5A2的表达。此外，音猬因子（SHh）/Gli1表达增加显著上调波形蛋白基因，E-钙黏蛋白显著降低。EIF5A2敲低部分逆转了人工过表达SHh诱导的细胞增殖和迁移，并抑制了过表达SHh的胰腺癌细胞中的上皮-间质转化过程（P<0.05）。
结论
我们的数据在胰腺癌细胞中建立了一种Gli1对EIF5A2基因的新型顺式调控转录机制。因此，EIF5A2癌基因效应可纳入Hh信号通路的促癌分子网络。
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