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

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Authors	PICHLER M. STIEGELBAUER V. VYCHYTILOVÁ Petra IVAN C. LING H. WINTER E. ZHANG X.N. GOBLIRSCH M. WULF-GOLDENBERG A. OHTSUKA M. HAYBAECK J. SVOBODA M. OKUGAWA Y. GERGER A. HOEFLER G. GOEL A. SLABÝ Ondřej CALIN G.A.
Year of publication	2017
Type	Article in Periodical
Magazine / Source	Clinical cancer research
MU Faculty or unit	Central European Institute of Technology
Citation
web	http://clincancerres.aacrjournals.org/content/23/5/1323
Doi	http://dx.doi.org/10.1158/1078-0432.CCR-16-0497
Keywords	ANTI-EGFR THERAPY; TUMOR-GROWTH; COLON-CANCER; MICRORNA SIGNATURES; PREDICTIVE-VALUE; STAGE-II; METASTASIS; EXPRESSION; PROGRESSION; BIOMARKER
Description	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 pre-specified 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: SixmiRNAs (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. (C) 2016 AACR.
Related projects:	CEITEC - Central European Institute of Technology