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

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2016-10, Vol.94 (10), p.1129-1141
• Main Authors: Zheng, Guopei, Li, Nan, Jia, Xiaoting, Peng, Cong, Luo, Liyun, Deng, Yingen, Yin, Jiang, Song, Ying, Liu, Hao, Lu, Minying, Zhang, Zhijie, Gu, Yixue, He, Zhimin
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Cell Adhesion Molecule-1; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell Line, Tumor; Drug Resistance, Neoplasm - genetics; Gene Expression Regulation, Neoplastic; Human Genetics; Humans; Immunoglobulins - genetics; Immunoglobulins - metabolism; Internal Medicine; MicroRNAs - metabolism; Molecular Medicine; N-Myc Proto-Oncogene Protein - genetics; N-Myc Proto-Oncogene Protein - metabolism; Original Article; Prognosis; RNA, Messenger - metabolism; Tongue Neoplasms - genetics; Tongue Neoplasms - metabolism
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-016-1417-0

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.