GEP oncogene promotes cell proliferation through YAP activation in ovarian cancer
GEP oncogene promotes cell proliferation through YAP activation in ovarian cancer
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DOI：
10.1038/onc.2015.505
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发表时间：
2016-08-01
期刊：
影响因子：
8
通讯作者：
Kato, K.
中科院分区：
文献类型：
--
作者：
Yagi, H.;Asanoma, K.;Kato, K.
G蛋白偶联受体(GPCRs)及其配体在人类恶性肿瘤的发生发展中起着重要作用。Gα(12)和Gα(13)分别由GNA12和GNA13编码，被称为GEP癌基因，与肿瘤的进展有关。然而，Gα(12/13)激活促进癌症进展的分子机制尚未完全阐明。在这里，我们证明了Gα12/13在人卵巢癌组织中的高表达。在所研究的卵巢癌细胞系中，Gα(12/13)的激活不能促进细胞的迁移。相反，Gα(12/13)激活促进了细胞生长。我们使用了一种合成生物学的方法，使用嵌合的G蛋白和仅由人工配体激活的GPCRs来选择性地触发特定G蛋白下游的信号通路。我们发现，Gα(12/13)通过激活转录共激活因子YAP促进卵巢癌细胞的增殖，YAP是河马信号通路的关键组成部分。此外，我们还发现，用短发夹状RNA或一种特定的抑制剂抑制YAP可以阻止卵巢癌细胞的生长。因此，YAP可能是卵巢癌合适的治疗靶点。
G-protein-coupled receptors (GPCRs) and their ligands function in the progression of human malignancies. G alpha(12) and G alpha(13), encoded by GNA12 and GNA13, respectively, are referred to as the GEP oncogene and are implicated in tumor progression. However, the molecular mechanisms by which G alpha(12/13) activation promotes cancer progression are not fully elucidated. Here, we demonstrate elevated expression of G alpha 12/13 in human ovarian cancer tissues. G alpha(12/13) activation did not promote cellular migration in the ovarian cancer cell lines examined. Rather, G alpha(12/13) activation promoted cell growth. We used a synthetic biology approach using chimeric G proteins and GPCRs activated solely by artificial ligands to selectively trigger signaling pathways downstream of specific G proteins. We found that G alpha(12/13) promotes proliferation of ovarian cancer cells by activating the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway. Furthermore, we reveal that inhibition of YAP by short hairpin RNA or a specific inhibitor prevented the growth of ovarian cancer cells. Therefore, YAP may be a suitable therapeutic target in ovarian cancer.