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

M. Pichler, V. Stiegelbauer, P. Vychytilova-Faltejskova, C. Ivan, H. Ling, E. Winter, X. Zhang, M. Goblirsch, A. Wulf-Goldenberg, M. Ohtsuka, J. Haybaeck, M. Svoboda, Y. Okugawa, A. Gerger, G. Hoefler, A. Goel, O. Slaby, GA. Calin,

. 2017 ; 23 (5) : 1323-1333. [pub] 20160906

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc18011029

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 situhybridization 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 cellsin vitroand metastases formationin 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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$a Purpose: Characterization of colorectal cancer transcriptome by high-throughput techniques has enabled the discovery of several differentially expressed genes involving previously unreported miRNA abnormalities. Here, we followed a systematic approach on a global scale to identify miRNAs as clinical outcome predictors and further validated them in the clinical and experimental setting.Experimental Design:Genome-wide miRNA sequencing data of 228 colorectal cancer patients from The Cancer Genome Atlas dataset were analyzed as a screening cohort to identify miRNAs significantly associated with survival according to stringent prespecified criteria. A panel of six miRNAs was further validated for their prognostic utility in a large independent validation cohort (n= 332).In situhybridization and functional experiments in a panel of colorectal cancer cell lines and xenografts further clarified the role of clinical relevant miRNAs.Results:Six miRNAs (miR-92b-3p, miR-188-3p, miR-221-5p, miR-331-3p, miR-425-3p, and miR-497-5p) were identified as strong predictors of survival in the screening cohort. High miR-188-3p expression proves to be an independent prognostic factor [screening cohort: HR = 4.137; 95% confidence interval (CI), 1.568-10.917;P= 0.004; validation cohort: HR = 1.538; 95% CI, 1.107-2.137;P= 0.010, respectively]. Forced miR-188-3p expression increased migratory behavior of colorectal cancer cellsin vitroand metastases formationin vivo(P< 0.05). The promigratory role of miR-188-3p is mediated by direct interaction with MLLT4, a novel identified player involved in colorectal cancer cell migration.Conclusions:miR-188-3p is a novel independent prognostic factor in colorectal cancer patients, which can be partly explained by its effect on MLLT4 expression and migration of cancer cells.Clin Cancer Res; 23(5); 1323-33. ©2016 AACR.
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$a Stiegelbauer, Verena $u Division of Oncology, Department of Internal Medicine, Medical University of Graz (MUG), Graz, Austria. Research Unit for Non-coding RNAs and Genome Editing, Medical University of Graz (MUG), Graz, Austria.
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$a Vychytilova-Faltejskova, Petra $u Molecular Oncology II - Solid Cancers, Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic. Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
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$a Ivan, Cristina $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. The Center for RNA Interference and Non-coding RNAs, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
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$a Ling, Hui $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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$a Winter, Elke $u Institute of Pathology, Medical University of Graz (MUG), Graz, Austria.
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$a Zhang, Xinna $u The Center for RNA Interference and Non-coding RNAs, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
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$a Goblirsch, Matthew $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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$a Wulf-Goldenberg, Annika $u Experimental Pharmacology & Oncology GmbH, EPO, Berlin-Buch, Germany.
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$a Ohtsuka, Masahisa $u Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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$a Svoboda, Marek $u Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
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$a Okugawa, Yoshinaga $u Center for Gastrointestinal Research and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
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$a Gerger, Armin $u Division of Oncology, Department of Internal Medicine, Medical University of Graz (MUG), Graz, Austria.
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$a Hoefler, Gerald $u Institute of Pathology, Medical University of Graz (MUG), Graz, Austria.
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$a Goel, Ajay $u Center for Gastrointestinal Research and Center for Epigenetics, Cancer Prevention and Cancer Genomics, Baylor Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
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$a Slaby, Ondrej $u 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.
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