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
- dospělí MeSH
- homeodoménové proteiny genetika MeSH
- kolorektální nádory genetika patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů MeSH
- mikro RNA genetika MeSH
- myši MeSH
- N-acetylgalaktosaminyltransferasy genetika MeSH
- nádorové buněčné linie MeSH
- pohyb buněk genetika MeSH
- polypeptid-N-acetylgalaktosaminyltransferasa MeSH
- přežití bez známek nemoci MeSH
- proliferace buněk genetika MeSH
- regulace genové exprese u nádorů genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- homeodoménové proteiny MeSH
- HOXB7 protein, human MeSH Prohlížeč
- mikro RNA MeSH
- MIRN196 microRNA, human MeSH Prohlížeč
- N-acetylgalaktosaminyltransferasy 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
- genom lidský MeSH
- HCT116 buňky MeSH
- karcinogeneze genetika MeSH
- kineziny genetika MeSH
- kolorektální nádory genetika patologie MeSH
- lidé MeSH
- mikro RNA genetika izolace a purifikace MeSH
- myosiny genetika MeSH
- myši MeSH
- nádorové biomarkery genetika MeSH
- prognóza MeSH
- transkriptom genetika MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- AFDN protein, human MeSH Prohlížeč
- kineziny MeSH
- mikro RNA MeSH
- MIRN188 microRNA, human MeSH Prohlížeč
- myosiny MeSH
- nádorové biomarkery MeSH
