Purpose: miR-196b-5p has been previously implicated in malignant transformation; however, its role in colorectal cancer has not been fully explored. In this study, we examine the clinical and biological relevance of miR-196b-5p, and the molecular pathways regulated by miR-196b-5p in colorectal cancer.Experimental Design: miR-196b-5p expression was quantitated by qRT-PCR in 2 independent cohorts composed of 292 patients with colorectal cancer in total, to explore its biomarker potential. Transient and stable gain- and loss-of-function experiments were conducted in a panel of colorectal cancer cell lines and mice, to evaluate the impact of miR-196b-5p on proliferation, chemosensitivity, migration/invasion, and metastases formation in vitro and in vivo The molecular pathways influenced by miR-196b-5p were characterized using whole transcriptome profiling, in silico target prediction tools, luciferase interaction assays, and phenocopy/rescue gene knockdown experiments.Results: Low miR-196b-5p expression was significantly associated with metastases and poor outcomes in 2 independent colorectal cancer patient cohorts (P < 0.05, log-rank test). miR-196b-5p inhibition led to significantly increased colorectal cancer cell migration/invasion and metastases formation in mice, whereas ectopic overexpression showed the opposite phenotype. Molecular profiling and target confirmation identified an interaction between miR-196b-5p and HOXB7 and GALNT5, which in turn regulated colorectal cancer cell migration.Conclusions: The association of low levels of miR-196b-5p and poor prognosis in patients with colorectal cancer can be explained by its influence on cancer cell migration and metastases formation. miR-196b-5p has an impact on colorectal cancer progression pathways through direct interaction with genes involved in cancer cell migration. Clin Cancer Res; 23(17); 5255-66. ©2017 AACR.

Academic Surgery University of Southampton Southampton United Kingdom

Center for Biomarker Research in Medicine Graz Austria

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute Czech Republic

Department of Experimental Therapeutics The University of Texas MD Anderson Cancer Center Houston Texas

Department of Pathology Otto von Guericke University Magdeburg Leipziger Str 44 D 39120 Magdeburg Germany

Department of Phoniatrics ENT University Hospital Medical University of Graz Graz Austria

Division of Haematology Department of Internal Medicine Medical University of Graz Austria

Division of Oncology Department of Internal Medicine Medical University of Graz Graz Austria

Experimental Pharmacology and Oncology GmbH EPO Berlin Germany

Institute of Human Genetics Medical University of Graz Graz Austria

Institute of Pathology Medical University of Graz Graz Austria

Molecular Oncology 2 Solid Cancers Molecular Medicine Central European Institute of Technology Masaryk University Brno Czech Republic

Research Unit for Non Coding RNAs and Genome Editing Medical University of Graz Graz Austria

The Center for RNA Interference and Non coding RNAs The University of Texas MD Anderson Cancer Center Houston Texas

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