miR-27a inhibits cervical adenocarcinoma progression by downregulating the TGF-βRI signaling pathway.
miR-27a inhibits cervical adenocarcinoma progression by downregulating the TGF-βRI signaling pathway.
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miR-27a通过下调TGF-beta RI信号通路抑制宫颈腺癌进展
DOI：
10.1038/s41419-018-0431-2
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发表时间：
2018-03-12
影响因子：
9
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Fang F;Huang B;Sun S;Xiao M;Guo J;Yi X;Cai J;Wang Z
高危型人乳头瘤病毒感染是宫颈癌恶变的关键，并可抑制宿主miR-27 a的表达。我们研究了miR-27 a在宫颈癌进展中的作用和机制。miR-27 a在宫颈癌细胞系中减少，并且miR-27 a-agomir抑制HeLa（腺癌）细胞的细胞增殖、迁移和侵袭特性，但在SiHa细胞（鳞状细胞癌）中不抑制。荧光素酶分析显示miR-27 a直接靶向转化生长因子β受体I（TGF-βRI）的3′-UTR，下调TGF-β信号转导。TGF-βRI表达载体的共转染在很大程度上恢复了miR-27 a-agomir介导的TGF-β信号传导、细胞增殖、迁移和侵袭的抑制。miR-27 a-agomir在体内可抑制HeLa移植瘤的生长，下调肿瘤组织中TGF-βRI的表达和TGF-β信号转导。组织芯片分析显示miR-27 a在腺癌细胞中表达较低，而在鳞癌细胞中则无表达，且与TGF-βRI表达呈负相关。高TGF-βRI与深基质浸润和淋巴结转移有关。这些结果表明，miR-27 a通过抑制TGF-βRI信号通路在宫颈癌（尤其是腺癌）中发挥肿瘤抑制因子的作用。因此，提高miR-27 a的表达和功能可能是宫颈腺癌的一种新的治疗策略。
High-risk human papillomavirus infection is essential for the malignant transformation of cervical cancer and can inhibit host miR-27a expression. We investigated the role and mechanism of miR-27a in cervical cancer progression. miR-27a is decreased in cervical cancer cell lines and miR-27a-agomir inhibited the cell proliferation, migration, and invasion properties of HeLa (adenocarcinoma) cells, but not in SiHa cells (squamous cell carcinoma). Luciferase assays revealed that miR-27a directly targets the 3′-UTR of transforming growth factor beta receptor I (TGF-βRI) and downregulates TGF-β signaling. The co-transfection of a TGF-βRI expression vector largely restored the inhibition of TGF-β signaling, cell proliferation, migration, and invasion mediated by miR-27a-agomir. Also, miR-27a-agomir slows down the growth of subcutaneous HeLa xenografts and downregulates the TGF-βRI expression and TGF-β signaling in tumor in vivo. Tissue microarray analysis revealed a low miR-27a level in adenocarcinoma cells, but not in squamous cell carcinoma cells, which was negatively associated with TGF-βRI expression. High TGF-βRI correlated with deep stromal invasion and lymph node metastasis. These results suggest that miR-27a acts as a tumor suppressor in cervical cancer, especially in adenocarcinoma, by inhibiting TGF-βRI signaling pathway. Thus, enhancing miR-27a expression and function may be a novel treatment strategy for cervical adenocarcinoma.
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