miR-190-Mediated Downregulation of PHLPP Contributes to Arsenic-Induced Akt Activation and Carcinogenesis
miR-190-Mediated Downregulation of PHLPP Contributes to Arsenic-Induced Akt Activation and Carcinogenesis
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DOI：
10.1093/toxsci/kfr188
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发表时间：
2011-10-01
影响因子：
3.8
通讯作者：
Chen, Fei
中科院分区：
文献类型：
--
作者：
Beezhold, Kevin;Liu, Jia;Chen, Fei
三价砷（As(3+)）对最近发现的非编码小rna（主要是microRNAs）的调控作用，目前还没有研究。在本研究中，我们提供的证据表明，As（3+）是人支气管上皮细胞中miR-190表达的有效诱导剂。As（3+）对miR-190的诱导是浓度依赖性的，与miR-190宿主基因talin 2的表达有关，talin 2是一种编码高分子量细胞骨架蛋白的基因。As（3+）诱导的miR-190水平升高能够下调PH结构域富亮氨酸重复蛋白磷酸酶（PHLPP）的翻译，PHLPP是Akt信号的负调节因子。这种下调是通过miR-190与PHLPP mRNA的3'-UTR区直接相互作用发生的，导致PHLPP蛋白表达减少，从而导致Akt调控蛋白血管内皮生长因子（vascular endothelial growth factor）的激活和表达增强。通过软琼脂中不依赖锚定的细胞生长可以确定，miR-190本身过表达能够促进细胞的增殖和恶性转化。因此，这些数据表明miR-190的诱导是As（3+）诱导癌变的关键机制之一。
The role of trivalent arsenic (As(3+)) on the regulation of the recently identified noncoding small RNAs, mainly microRNAs, has not been explored so far. In the present study, we provide evidence showing that As(3+) is a potent inducer for the expression of miR-190 in human bronchial epithelial cells. The induction of miR-190 by As(3+) is concentration dependent and associated with the expression of the host gene of miR-190, talin 2, a gene encoding a high-molecular-weight cytoskeletal protein. The elevated level of miR-190 induced by As(3+) is capable of downregulating the translation of the PH domain leucine-rich repeat protein phosphatase (PHLPP), a negative regulator of Akt signaling. Such a downregulation is occurred through direct interaction of the miR-190 with the 3'-UTR region of the PHLPP mRNA, leading to a diminished PHLPP protein expression and consequently, an enhanced Akt activation and expression of vascular endothelial growth factor, an Akt-regulated protein. Overexpression of miR-190 itself is able to enhance proliferation and malignant transformation of the cells as determined by anchorage-independent growth of the cells in soft agar. Accordingly, the data presented suggest that induction of miR-190 is one of the key mechanisms in As(3+)-induced carcinogenesis.