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Theranostics 2019; 9(26):8409-8425. doi:10.7150/thno.36605 This issue Cite

Research Paper

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

Lina Sun^1,2*, Ying Fang^1*, Xin Wang^2,3*, Yanan Han^1*, Feng Du², Cunxi Li⁴, Huaying Hu^4,5, Hao Liu², Qi Liu⁶, Jing Wang⁶, Junrong Liang^2,3, Ping Chen^2,3, Hongbin Yang¹, Yongzhan Nie², Kaichun Wu², Daiming Fan², Robert J. Coffey^7,8, Yuanyuan Lu^2✉, Xiaodi Zhao^2,9✉, Xin Wang^2,3✉

1. The Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an 710003, China.
2. State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, China.
3. Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
4. Jiaen Genetics Laboratory, Beijing Jiaen Hospital, Beijing 100191, China.
5. School of Medicine, Xiamen University, Xiamen 361002, China.
6. Department of Biomedical Informatics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
7. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
8. Department of Veterans Affairs Medical Center, Nashville, Tennessee 37212, USA.
9. National Institute of Biological Sciences, Beijing 102206, China.
*Authors share co-first authorship.

✉ Corresponding authors: Y.L. (luyuandreamercom), X.Z. (leedyzhaoedu.cn), or X.W. (wangxedu.cn).

Abstract

Introduction: 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.

Methods: miR-302a expression in CRC cell lines and patient tissue microarrays was analyzed by qPCR and fluorescence in situ hybridization. The roles of miR-302a in metastasis and cetuximab (CTX) resistance were evaluated both in vitro and in vivo. 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.

Results: 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.

Conclusions: 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.

Keywords: miRNA, colorectal cancer, metastasis, targeted therapy, drug resistance.

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