Genome-Wide miRNA analysis identifies miR- 188-3p as a novel prognostic markerandmolecular factor involved in colorectal carcinogenesis

Martin Pichler, Verena Stiegelbauer, Petra Vychytilova-Faltejskova, Cristina Ivan, Hui Ling, Elke Winter, Xinna Zhang, Matthew Goblirsch, Annika Wulf-Goldenberg, Masahisa Ohtsuka, Johannes Haybaeck, Marek Svoboda, Yoshinaga Okugawa, Armin Gerger, Gerald Hoefler, Ajay Goel, Ondrej Slaby, George Adrian Calin

Research output: Contribution to journalArticle

38 Scopus citations

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: 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.

Original languageEnglish (US)
Pages (from-to)1323-1333
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number5
DOIs
StatePublished - Mar 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Pichler, M., Stiegelbauer, V., Vychytilova-Faltejskova, P., Ivan, C., Ling, H., Winter, E., Zhang, X., Goblirsch, M., Wulf-Goldenberg, A., Ohtsuka, M., Haybaeck, J., Svoboda, M., Okugawa, Y., Gerger, A., Hoefler, G., Goel, A., Slaby, O., & Calin, G. A. (2017). Genome-Wide miRNA analysis identifies miR- 188-3p as a novel prognostic markerandmolecular factor involved in colorectal carcinogenesis. Clinical Cancer Research, 23(5), 1323-1333. https://doi.org/10.1158/1078-0432.CCR-16-0497