Abstract
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.
Highlights
Colorectal cancer is one of the most common causes of cancer-related deaths worldwide [1]
This study reveals functional and mechanistic links between miRNA-224 and the tumor suppressors PH domain leucine-rich-repeats protein phosphatase 1 (PHLPP1) and PHLPP2 in the pathogenesis of colorectal cancer. miR-224 plays important roles in the regulation of cell proliferation and tumor growth in colorectal cancer, and has potential as a prognostic marker or therapeutic target for colorectal cancer
Results miR-224 is overexpressed in colorectal cancer The expression of miR-224 was detected in 43 pairs of colorectal cancer biopsies and their matched adjacent normal tissues, and 77 cases of fresh colorectal cancer biopsies by real-time PCR revealed that miR-224 was significantly overexpressed in 76.7% (33/43) of the colorectal cancer tissue samples examined (T/N > 2-fold) compared to the matched adjacent normal tissues from the same patient, with up to 68-fold increases observed in the colorectal cancer tissue samples (Fig. 1A)
Summary
Colorectal cancer is one of the most common causes of cancer-related deaths worldwide [1]. Progress has been made in diagnostic and therapeutic strategies, the clinical outcome and prognosis of colorectal cancer patients with advanced stage disease still remains poor [2]. Authors' Affiliations: Departments of 1Pathology and 2Gastroenterology, Nanfang Hospital, Southern Medical University; 3Department of Pathology, School of Basic Medical Sciences; 4State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong; and 5Department of Gastroenterology, The Second Affiliated Hospital, University of South China, HengYang, Hunan, China. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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