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.

• MeSH
• Adult MeSH
• Homeodomain Proteins genetics   MeSH
• Colorectal Neoplasms genetics   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• MicroRNAs genetics   MeSH
• Mice MeSH
• N-Acetylgalactosaminyltransferases genetics   MeSH
• Cell Line, Tumor MeSH
• Cell Movement genetics   MeSH
• Polypeptide N-acetylgalactosaminyltransferase MeSH
• Disease-Free Survival MeSH
• Cell Proliferation genetics   MeSH
• Gene Expression Regulation, Neoplastic genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Mice MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Homeodomain Proteins MeSH
• HOXB7 protein, human MeSH Browser
• MicroRNAs MeSH
• MIRN196 microRNA, human MeSH Browser
• N-Acetylgalactosaminyltransferases MeSH

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: 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 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. Clin Cancer Res; 23(5); 1323-33. ©2016 AACR.

• MeSH
• Genome, Human MeSH
• HCT116 Cells MeSH
• Carcinogenesis genetics   MeSH
• Kinesins genetics   MeSH
• Colorectal Neoplasms genetics   pathology   MeSH
• Humans MeSH
• MicroRNAs genetics   isolation & purification   MeSH
• Myosins genetics   MeSH
• Mice MeSH
• Biomarkers, Tumor genetics   MeSH
• Prognosis MeSH
• Transcriptome genetics   MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• AFDN protein, human MeSH Browser
• Kinesins MeSH
• MicroRNAs MeSH
• MIRN188 microRNA, human MeSH Browser
• Myosins MeSH
• Biomarkers, Tumor MeSH