miR-196b-5p Regulates Colorectal Cancer Cell Migration and Metastases through Interaction with HOXB7 and GALNT5

Abstract

<b>Purpose:</b> 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.<b>Experimental Design:</b> 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 <i>in vitro</i> and <i>in vivo</i> The molecular pathways influenced by miR-196b-5p were characterized using whole transcriptome profiling, <i>in silico</i> target prediction tools, luciferase interaction assays, and phenocopy/rescue gene knockdown experiments.<b>Results:</b> Low miR-196b-5p expression was significantly associated with metastases and poor outcomes in 2 independent colorectal cancer patient cohorts (<i>P</i> < 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 <i>HOXB7</i> and <i>GALNT5,</i> which in turn regulated colorectal cancer cell migration.<b>Conclusions:</b> 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. <i>Clin Cancer Res; 23(17); 5255-66. ©2017 AACR</i>.