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

• Published in: Theranostics 2019-01, Vol.9 (26), p.8409-8425
• Main Authors: Sun, Lina, Fang, Ying, Wang, Xin, Han, Yanan, Du, Feng, Li, Cunxi, Hu, Huaying, Liu, Hao, Liu, Qi, Wang, Jing, Liang, Junrong, Chen, Ping, Yang, Hongbin, Nie, Yongzhan, Wu, Kaichun, Fan, Daiming, Coffey, Robert J, Lu, Yuanyuan, Zhao, Xiaodi
• Format: Article
• Language: English
• Subjects: Cell culture; Cloning; Colorectal cancer; Cytotoxicity; Drug resistance; Gene expression; Laboratory animals; Medical prognosis; Metastasis; MicroRNAs; Monoclonal antibodies; Patients; Research Paper; Targeted cancer therapy
• ISSN: 1838-7640; 1838-7640
• 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.