MYCN-mediated miR-21 overexpression enhances chemo-resistance via targeting CADM1 in tongue cancer
MYCN-mediated miR-21 overexpression enhances chemo-resistance via targeting CADM1 in tongue cancer
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MYCN介导的miR-21过表达通过靶向CADM1增强舌癌的化疗耐药性
DOI：
10.1007/s00109-016-1417-0
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发表时间：
2016-10-01
影响因子：
4.7
通讯作者：
He, Zhimin
中科院分区：
文献类型：
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作者：
Zheng, Guopei;Li, Nan;He, Zhimin
摘要化疗耐药仍然是肿瘤治疗成功的主要障碍。在此之前，我们发现miR-21- 5 p在舌癌耐药细胞系Tca 8113/PYM中表达上调。然而，miR-21上调的机制及其在TC化疗耐药性中的作用仍不清楚。在这里，我们证明了miR-21的功能抑制使TC细胞对化疗敏感。与此一致，过表达的miR-21增强了TC细胞的化疗耐药性。我们发现miR-21直接靶向CADM 1表达，其在耐药TC细胞中下调。恢复CADM 1表达使TC细胞对化疗敏感，但CADM 1敲低诱导化疗耐药。在机械上，CADM 1与BMI 1相互作用以抑制其核转位。此外，在TC耐药细胞中过表达的MYCN可直接与miR-21启动子结合，上调TC细胞中miR-21的表达。重要的是，在TC组织中，miR-21和CADM 1的表达水平呈负相关，但MYCN和miR-21呈正相关。高水平的miR-21和MYCN以及低水平的CADM 1与TC患者的不良预后相关。最后，我谨指出，我们的研究表明MYCN/miR-21/CADM 1轴在TC患者的化疗耐药性中起重要作用，并可能导致有希望的预后生物标志物和新的治疗策略，以提高TC患者的化疗疗效。通过靶向CADM 1在舌癌细胞中产生耐药性。CADM 1使舌癌细胞对化疗敏感。CADM 1与BMI 1相互作用，抑制其核增殖。MYCN转录调节miR-21表达。MYCN/miR-21/CADM 1轴失调与TC患者预后不良相关。
AbstractChemo-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 themiR-21promoter 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 messagesMiR-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.