microRNA-224 Promotes Cell Proliferation and Tumor Growth in Human Colorectal Cancer by Repressing PHLPP1 and PHLPP2
microRNA-224 Promotes Cell Proliferation and Tumor Growth in Human Colorectal Cancer by Repressing PHLPP1 and PHLPP2
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microRNA-224 通过抑制 PHLPP1 和 PHLPP2 促进人结直肠癌细胞增殖和肿瘤生长
DOI：
10.1158/1078-0432.ccr-13-0244
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发表时间：
2013-09-01
影响因子：
11.5
通讯作者：
Ding, Yan-Qing
中科院分区：
文献类型：
--
作者：
Liao, Wen-Ting;Li, Ting-Ting;Ding, Yan-Qing
目的：探讨microRNA-224 （miR-224）在结直肠癌中的临床病理意义、作用及机制。实验设计：采用Real-time PCR定量miR-224的表达。在110例结直肠癌患者中评估miR-224与临床病理特征和生存的关系。通过体外和体内实验研究miR-224在结直肠癌中的作用。荧光素酶报告基因检测证实了靶基因的相关性。结果：miR-224在结直肠癌中过表达。miR-224的高水平表达与侵袭性表型和不良预后显著相关。过表达miR-224在体外促进结直肠癌细胞增殖，在体内促进肿瘤生长。具体来说，miR-224通过激活AKT/FOXO3a信号，下调p21Cip1和p27Kip1，上调cyclin D1，加速了G1-S阶段的转变。此外，PH结构域富含亮氨酸重复序列的蛋白磷酸酶1 （PHLPP1）和PHLPP2， PI3K/AKT信号的拮抗剂，被证实是miR-224的真正靶点。miR-224直接靶向PHLPP1和PHLPP2 mrna的3 ' -非翻译区，抑制其表达。结论：本研究揭示了miRNA-224与肿瘤抑制因子PHLPP1和PHLPP2在结直肠癌发病中的功能和机制联系。miR-224不仅在大肠癌中调控细胞增殖和肿瘤生长中发挥重要作用，而且具有作为大肠癌预后标志物或治疗靶点的潜力。临床癌症研究；19 (17);4662 - 72。AACR©2013。
Purpose: To investigate the clinicopathologic significance, role, and mechanism of action of microRNA-224 (miR-224) in colorectal cancer. Experimental Design: Real-time PCR was used to quantify miR-224 expression. The association of miR-224 with the clinicopathologic features and survival was evaluated in 110 colorectal cancer patients. The role of miR-224 in colorectal cancer was investigated using in vitro and in vivo assays. Luciferase reporter assays were conducted to confirm target gene associations. Results: miR-224 was overexpressed in colorectal cancer. High-level expression of miR-224 was significantly associated with an aggressive phenotype and poor prognosis. Overexpression of miR-224 promoted colorectal cancer cell proliferation in vitro and tumor growth in vivo. Specifically, miR-224 accelerated the G1–S phase transition through activation of AKT/FOXO3a signaling, downregulation of p21Cip1 and p27Kip1, and upregulation of cyclin D1. Moreover, both PH domain leucine-rich-repeats protein phosphatase 1 (PHLPP1) and PHLPP2, antagonists of PI3K/AKT signaling, were confirmed as bona fide targets of miR-224. miR-224 directly targeted the 3′-untranslated regions of the PHLPP1 and PHLPP2 mRNAs and repressed their expression. Conclusion: This study reveals functional and mechanistic links between miRNA-224 and the tumor suppressors PHLPP1 and PHLPP2 in the pathogenesis of colorectal cancer. miR-224 not only plays important roles in the regulation of cell proliferation and tumor growth in colorectal cancer, but also has potential as a prognostic marker or therapeutic target for colorectal cancer. Clin Cancer Res; 19(17); 4662–72. ©2013 AACR.