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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.

Author information

1
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. gcalin@mdanderson.org martin.pichler@medunigraz.at.
2
Division of Oncology, Department of Internal Medicine, Medical University of Graz (MUG), Graz, Austria.
3
Research Unit for Non-coding RNAs and Genome Editing, Medical University of Graz (MUG), Graz, Austria.
4
Molecular Oncology II - Solid Cancers, Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
5
Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
6
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
The Center for RNA Interference and Non-coding RNAs, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
8
Institute of Pathology, Medical University of Graz (MUG), Graz, Austria.
9
Experimental Pharmacology & Oncology GmbH, EPO, Berlin-Buch, Germany.
10
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.

Abstract

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.

PMID:
27601590
PMCID:
PMC5544252
DOI:
10.1158/1078-0432.CCR-16-0497
[Indexed for MEDLINE]
Free PMC Article

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