Genome-Wide miRNA Analysis Identifies miR-188-3p as a Novel Prognostic Marker and Molecular Factor Involved in Colorectal Carcinogenesis.
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.
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. gcalin@mdanderson.org martin.pichler@medunigraz.at.|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.
Martin
M
Pichler
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.
Verena
V
Stiegelbauer
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.
Petra
P
Vychytilova-Faltejskova
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.
Cristina
C
Ivan
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Hui
H
Ling
Institute of Pathology, Medical University of Graz (MUG), Graz, Austria.
Elke
E
Winter
The Center for RNA Interference and Non-coding RNAs, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
Xinna
X
Zhang
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Matthew
M
Goblirsch
Experimental Pharmacology & Oncology GmbH, EPO, Berlin-Buch, Germany.
Annika
A
Wulf-Goldenberg
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Masahisa
M
Ohtsuka
Institute of Pathology, Medical University of Graz (MUG), Graz, Austria.
Johannes
J
Haybaeck
Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
Marek
M
Svoboda
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.
Yoshinaga
Y
Okugawa
Division of Oncology, Department of Internal Medicine, Medical University of Graz (MUG), Graz, Austria.
Armin
A
Gerger
Institute of Pathology, Medical University of Graz (MUG), Graz, Austria.
Gerald
G
Hoefler
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.
Ajay
A
Goel
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.
Ondrej
O
Slaby
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. gcalin@mdanderson.org martin.pichler@medunigraz.at.|The Center for RNA Interference and Non-coding RNAs, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
George Adrian
GA
Calin
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D015894:Genome, Human; D045325:HCT116 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000302:isolation & purification; D009218:Myosins / Q000235:genetics*; D011379:Prognosis; D059467:Transcriptome / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
C095516:AFDN protein, human; D014408:Biomarkers, Tumor; C584093:MIRN188 microRNA, human; D035683:MicroRNAs; D009218:Myosins; D016547:Kinesins