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MYCN-mediated miR-21 overexpression enhances chemo-resistance via targeting CADM1 in tongue cancer

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Abstract

Chemo-resistance is still a major obstacle in successful cancer treatment. Previously, we found that miR-21 (miR-21-5p) was upregulated in drug-resistant tongue cancer (TC) cell line Tca8113/PYM. However, the mechanisms for miR-21 upregulation and its role in chemo-resistance in TC remain unclear. Here, we demonstrated that functional inhibition of miR-21 sensitized TC cells to chemotherapy. In agreement, overexpressed miR-21 enhanced chemo-resistance in TC cells. We found that miR-21 directly targeted CADM1 expression, which was downregulated in drug-resistant TC cells. Restored CADM1 expression sensitized TC cells to chemotherapy, but CADM1 knockdown induced chemo-resistance. Mechanically, CADM1 interacted with BMI1 to inhibit its nuclear translocation. Moreover, MYCN which was overexpressed in drug-resistant TC cells directly bound to the miR-21 promoter to upregulated miR-21 expression in TC cells. Importantly, the expression levels of miR-21 and CADM1 negatively correlated, but MYCN and miR-21 positively correlated in TC tissues. High levels of miR-21 and MYCN and low level of CADM1 were associated with poor prognosis in TC patients. In conclusion, our study suggests an important role of the MYCN/miR-21/CADM1 axis in chemo-resistance in TC patients and may lead to promising prognostic biomarkers and novel treatment strategies to improve the chemotherapeutic efficacy for TC patients.

Key messages

  • MiR-21 enhances chemo-resistance via targeting CADM1 in tongue cancer cells.

  • CADM1 sensitizes tongue cancer cells to chemotherapy.

  • CADM1 interacts with BMI1 to inhibit its nuclear translocation.

  • MYCN transcriptionally regulates miR-21 expression.

  • Dysregulated MYCN/miR-21/CADM1 axis associates with poor prognosis in TC patients.

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Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (30873088, 81272450, 81402196, 81401989), Natural Science Foundation of Gongdong Province (S2012010008995), and Doctoral Fund of Ministry of Education of China (20124423110003).

Author contribution

GZ, NL, XJ, CP, YD, JY, YS, and ML performed the research. HL and JZ statistically analyzed the experimental data. GZ and ZH designed the study and wrote the paper.

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Correspondence to Zhimin He.

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The study was approved by the ethics committee of the Cancer Center of Guangzhou Medical University.

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The authors declare that they have no conflicts of interest.

Authorship statement

This work is an original research and has not been submitted and is not under consideration for publication elsewhere, in whole or in part. All authors have read and approved to submit it to your journal.

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Zheng, G., Li, N., Jia, X. et al. MYCN-mediated miR-21 overexpression enhances chemo-resistance via targeting CADM1 in tongue cancer. J Mol Med 94, 1129–1141 (2016). https://doi.org/10.1007/s00109-016-1417-0

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  • DOI: https://doi.org/10.1007/s00109-016-1417-0

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