MicroRNA-410 Functions as a Tumor Suppressor by Targeting Angiotensin II Type 1 Receptor in Pancreatic Cancer
MicroRNA-410 Functions as a Tumor Suppressor by Targeting Angiotensin II Type 1 Receptor in Pancreatic Cancer
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MicroRNA-410 通过靶向胰腺癌中的血管紧张素 II 1 型受体发挥肿瘤抑制剂的作用
DOI：
10.1002/iub.1342
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发表时间：
2015-01-01
期刊：
影响因子：
4.6
通讯作者：
Gu, Chuan
中科院分区：
文献类型：
--
作者：
Guo, Rende;Gu, Jianhua;Gu, Chuan
microRNAs（miRNAs）在多种生物学过程中作为基因表达的关键调节因子，并与肿瘤发生密切相关。然而，miR-410在胰腺癌中的潜在分子机制仍然知之甚少。在这项研究中，我们发现miR-410过表达抑制胰腺癌细胞在体外和体内的生长以及细胞侵袭和迁移。miR-410还导致G1/S细胞周期停滞。然后，我们发现血管紧张素II 1型受体（AGTR 1）是miR-410的直接靶点，miR-410抑制AGTR 1的表达水平。相反，miR-410的抑制增加了AGTR 1的表达。AGTR 1的沉默抑制细胞生长和侵袭，类似于miR-410过表达。此外，我们发现血管紧张素II诱导血管内皮生长因子和激活ERK信号通路被miR-410阻断，类似于血管紧张素II抑制剂氯沙坦。miR-410过表达通过抑制CD 31表达抑制小鼠血管生成。ERK通路敲低抑制胰腺癌细胞增殖、侵袭和血管生成。最后，我们发现miR-410在胰腺癌组织中的表达低于邻近的非肿瘤组织，而AGTR 1在胰腺癌组织中的表达高于邻近的非肿瘤组织。Pearson相关分析显示miR-410和AGTR 1呈负相关。总之，我们的数据表明，miR-410通过下调AGTR 1（作为肿瘤抑制性miRNA）抑制胰腺癌生长、细胞侵袭、迁移和血管生成。此外，我们的研究结果表明，miR-410是胰腺癌患者潜在的诊断生物标志物和治疗靶点。(c)2015 IUBMB Life，67（1）：42-53，2015
MicroRNAs (miRNAs) act as key regulators of gene expression in diverse biological processes and are intimately involved in tumorigenesis. However, the underlying molecular mechanisms of miR-410 in pancreatic cancer remain poorly understood. In this study, we found that miR-410 overexpression suppressed pancreatic cancer cell growth in vitro and in vivo as well as cell invasion and migration. miR-410 also resulted in G1/S cell-cycle arrest. We then showed that angiotensin II type 1 receptor (AGTR1) was a direct target of miR-410, with miR-410 suppressing AGTR1 expression levels. In contrast, inhibition of miR-410 increased the expression of AGTR1. Silencing of AGTR1 inhibited cell growth and invasion, similar to miR-410 overexpression. In addition, we found that the induction of vascular endothelial growth factor and the activation of the ERK signaling pathway by angiotensin II were blocked by miR-410, similar to the angiotensin II inhibitor losartan. miR-410 overexpression inhibited angiogenesis in mice through the repression of CD31 expression. ERK pathway knockdown suppressed pancreatic cancer cell proliferation, invasion, and angiogenesis. Finally, we found that miR-410 was downregulated in pancreatic cancer tissues compared to adjacent nontumor tissues, whereas AGTR1 was upregulated in pancreatic cancer tissues. Pearson correlation analysis showed that miR-410 and AGTR1 were inversely expressed. In conclusion, our data indicate that miR-410 suppresses pancreatic cancer growth, cell invasion, migration, and angiogenesis via the downregulation of AGTR1, acting as a tumor-suppressive miRNA. In addition, our results suggest that miR-410 is a potential diagnostic biomarker and therapeutic target for patients with pancreatic cancer. (c) 2015 IUBMB Life, 67(1):42-53, 2015