microRNA-224 Promotes Cell Proliferation and Tumor Growth in Human Colorectal Cancer by Repressing PHLPP1 and PHLPP2

• Published in: Clinical cancer research 2013-09, Vol.19 (17), p.4662-4672
• Main Authors: LIAO, Wen-Ting, LI, Ting-Ting, CHI ZHANG, XIE, Yi-Jun, WANG, Jun-Xian, DING, Yan-Qing, WANG, Zheng-Gen, WANG, Shu-Yang, HE, Mei-Rong, YE, Ya-Ping, LU QI, CUI, Yan-Mei, PING WU, JIAO, Hong-Li
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Biological and medical sciences; Cell Proliferation; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Humans; Male; Medical sciences; MicroRNAs - biosynthesis; MicroRNAs - genetics; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nuclear Proteins - biosynthesis; Nuclear Proteins - genetics; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - genetics; Phosphoprotein Phosphatases - biosynthesis; Phosphoprotein Phosphatases - genetics; Signal Transduction - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-13-0244

To investigate the clinicopathologic significance, role, and mechanism of action of microRNA-224 (miR-224) in colorectal cancer. 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. 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. 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.