miR-302a Inhibits Metastasis and Cetuximab Resistance in Colorectal Cancer by Targeting NFIB and CD44.

Sun L, Fang Y, Wang X, Han Y, Du F, Li C, Hu H, Liu H, Liu Q, Wang J, Liang J, Chen P, Yang H, Nie Y, Wu K, Fan D, Coffey RJ, Lu Y, Zhao X, Wang X
Theranostics. 2019 9 (26): 8409-8425

PMID: 31754405 · PMCID: PMC6857048 · DOI:10.7150/thno.36605

: Metastasis and drug resistance contribute substantially to the poor prognosis of colorectal cancer (CRC) patients. However, the epigenetic regulatory mechanisms by which CRC develops metastatic and drug-resistant characteristics remain unclear. This study aimed to investigate the role of miR-302a in the metastasis and molecular-targeted drug resistance of CRC and elucidate the underlying molecular mechanisms. : miR-302a expression in CRC cell lines and patient tissue microarrays was analyzed by qPCR and fluorescence hybridization. The roles of miR-302a in metastasis and cetuximab (CTX) resistance were evaluated both and . Bioinformatic prediction algorithms and luciferase reporter assays were performed to identify the miR-302a binding regions in the NFIB and CD44 3'-UTRs. A chromatin immunoprecipitation assay was performed to examine NFIB occupancy in the ITGA6 promoter region. Immunoblotting was performed to identify the EGFR-mediated pathways altered by miR-302a. : miR-302a expression was frequently reduced in CRC cells and tissues, especially in CTX-resistant cells and patient-derived xenografts. The decreased miR-302a levels correlated with poor overall CRC patient survival. miR-302a overexpression inhibited metastasis and restored CTX responsiveness in CRC cells, whereas miR-302a silencing exerted the opposite effects. NFIB and CD44 were identified as novel targets of miR-302a. miR-302a inhibited the metastasis-promoting effect of NFIB that physiologically activates ITGA6 transcription. miR-302a restored CTX responsiveness by suppressing CD44-induced cancer stem cell-like properties and EGFR-mediated MAPK and AKT signaling. These results are consistent with clinical observations indicating that miR-302a expression is inversely correlated with the expression of its targets in CRC specimens. : Our findings show that miR-302a acts as a multifaceted regulator of CRC metastasis and CTX resistance by targeting NFIB and CD44, respectively. Our study implicates miR-302a as a candidate prognostic predictor and a therapeutic agent in CRC.

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MeSH Terms (13)

Caco-2 Cells Cetuximab Colorectal Neoplasms Drug Resistance, Neoplasm Gene Expression Regulation, Neoplastic HCT116 Cells Humans Hyaluronan Receptors In Vitro Techniques MicroRNAs Neoplasm Metastasis NFI Transcription Factors Signal Transduction

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