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Clin Cancer Res. 2017 Mar 1;23(5):1323-1333. doi: 10.1158/1078-0432.CCR-16-0497. Epub 2016 Sep 6.

Genome-Wide miRNA Analysis Identifies miR-188-3p as a Novel Prognostic Marker and Molecular Factor Involved in Colorectal Carcinogenesis.

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Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Division of Oncology, Department of Internal Medicine, Medical University of Graz (MUG), Graz, Austria.
Research Unit for Non-coding RNAs and Genome Editing, Medical University of Graz (MUG), Graz, Austria.
Molecular Oncology II - Solid Cancers, Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
The Center for RNA Interference and Non-coding RNAs, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
Institute of Pathology, Medical University of Graz (MUG), Graz, Austria.
Experimental Pharmacology & Oncology GmbH, EPO, Berlin-Buch, Germany.
Center for Gastrointestinal Research and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.


Purpose: Characterization of colorectal cancer transcriptome by high-throughput techniques has enabled the discovery of several differentially expressed genes involving previously unreported miRNA abnormalities. Here, we followed a systematic approach on a global scale to identify miRNAs as clinical outcome predictors and further validated them in the clinical and experimental setting.Experimental Design: Genome-wide miRNA sequencing data of 228 colorectal cancer patients from The Cancer Genome Atlas dataset were analyzed as a screening cohort to identify miRNAs significantly associated with survival according to stringent prespecified criteria. A panel of six miRNAs was further validated for their prognostic utility in a large independent validation cohort (n = 332). In situ hybridization and functional experiments in a panel of colorectal cancer cell lines and xenografts further clarified the role of clinical relevant miRNAs.Results: Six miRNAs (miR-92b-3p, miR-188-3p, miR-221-5p, miR-331-3p, miR-425-3p, and miR-497-5p) were identified as strong predictors of survival in the screening cohort. High miR-188-3p expression proves to be an independent prognostic factor [screening cohort: HR = 4.137; 95% confidence interval (CI), 1.568-10.917; P = 0.004; validation cohort: HR = 1.538; 95% CI, 1.107-2.137; P = 0.010, respectively]. Forced miR-188-3p expression increased migratory behavior of colorectal cancer cells in vitro and metastases formation in vivo (P < 0.05). The promigratory role of miR-188-3p is mediated by direct interaction with MLLT4, a novel identified player involved in colorectal cancer cell migration.Conclusions: miR-188-3p is a novel independent prognostic factor in colorectal cancer patients, which can be partly explained by its effect on MLLT4 expression and migration of cancer cells. Clin Cancer Res; 23(5); 1323-33. ©2016 AACR.

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