Overexpression of the c-Myc oncogene has been implicated in cancer stem cell - like (CSC) phenotypes and epithelial-to-mesenchymal transition (EMT) in cancer. However, the underlying molecular mechanism by which c-Myc regulates EMT and CSC potential in remains unclear. In the present study, we showed that the expression of c-Myc protein is inversely correlated with microRNA (miR)-200c expression in primary tumor samples from nasopharyngeal cancer (NPC) patients. We further demonstrated that Myc and miR-200c negatively regulate the expression each other in NPC cell lines. c-Myc transcriptionally repressed expression of miR-200c by directly binding to two E-box sites located within a 1 kb segment upstream of TSS of the miR-200c. In addition, miR-200c post-transcriptionally repressed expression of c-Myc by binding to its 3'-untranslated region, suggesting the existence of a negative feedback loop between Myc and miR-200c. Overexpression of c-Myc interfered with this feedback loop and activated the EMT program, induced CSC phenotypes, and enhanced drug sensitivity, whereas miR-200c could counteract these biological effects of c-Myc. Our results provide a novel mechanism governing c-Myc and miR-200c expression and indicate that either targeting c-Myc or restoring miR-200c expression would be a promising approach to overcome oncogenic role of c-Myc in NPC.

中文翻译：

---

新型的miR-200c / c-myc负调控反馈回路对于鼻咽癌的EMT过程，CSC生物学和药物敏感性至关重要。

c-Myc癌基因的过表达与癌症干细胞样（CSC）表型和上皮间质转化（EMT）有关。然而，尚不清楚c-Myc调控EMT和CSC潜能的潜在分子机制。在本研究中，我们显示了在鼻咽癌（NPC）患者的原发性肿瘤样本中c-Myc蛋白的表达与microRNA（miR）-200c表达呈负相关。我们进一步证明Myc和miR-200c在NPC细胞系中彼此负调控。c-Myc通过直接结合到位于miR-200c TSS上游1 kb片段内的两个E-box位点来转录抑制miR-200c的表达。此外，miR-200c通过与c-Myc的3'-非翻译区结合来抑制c-Myc的表达，这表明Myc和miR-200c之间存在负反馈回路。c-Myc的过表达干扰了该反馈回路并激活了EMT程序，诱导了CSC表型，并增强了药物敏感性，而miR-200c可以抵消c-Myc的这些生物学作用。我们的结果提供了控制c-Myc和miR-200c表达的新机制，并表明靶向c-Myc或恢复miR-200c表达将是克服c-Myc在NPC中的致癌作用的有前途的方法。