MicroRNA-196b-5p regulates colorectal cancer cell migration and metastases through interaction of HOXB7 and GALNT5

Purpose: MicroRNA-196b-5p (miR-196b-5p) has been previously implicated in malignant transformation, however, its role in colorectal cancer (CRC) has not been fully explored. In the current study, we examine the clinical and biological relevance of miR-196b-5p, and the molecular pathways regulated by miR-196b-5p in CRC. <p>Experimental design: MiR-196b-5p expression was quantitated by qRT-PCR in two independent cohorts comprised of 292 CRC patients in total, to explore its biomarker potential. Transient and stable gain and loss of function experiments were conducted in a panel of CRC cell lines and mice, to evaluate the impact of miR-196b-5p on proliferation, chemo-sensitivity, 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 pheno-copy/rescue gene knock-down experiments.</p> <p>Results: Low miR-196b-5p expression was significantly associated with metastases and poor outcomes in two independent CRC patient cohorts (p<0.05, log-rank test). MiR-196b-5p inhibition led to significantly increased CRC 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 regulate CRC cell migration.</p> <p>Conclusions: The association of low levels of miR-196b-5p and poor prognosis in CRC patients can be explained by its influence on cancer cell migration and metastases formation. MiR-196b-5p impacts CRC progression pathways through direct interaction with genes involved in cancer cell migration.

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