BRD7 expression and c-Myc activation forms a double-negative feedback loop that controls the cell proliferation and tumor growth of nasopharyngeal carcinoma by targeting oncogenic miR-141

• DOI: 10.1186/s13046-018-0734-2
• Publication Date: 2018-04-04T00:23:41Z
• Authors: Yukun Liu; Ran Zhao; Yanmei Wei; Mengna Li; Heran Wang; Weihong Niu; Yao Zhou; Yuanzheng Qiu; Songqing Fan; Yihao Zhan; Wei Xiong; Yanhong Zhou; Xiaoling Li; Zheng Li; Guiyuan Li; Ming Zhou
• Keywords: Male; Chromosomal Proteins, Non-Histone; Models, Biological; Proto-Oncogene Proteins c-myc; Mice; 03 medical and health sciences; Cell Line, Tumor; Nasopharyngeal carcinoma; C-Myc; Animals; Humans; Gene Regulatory Networks; RC254-282; Cell Proliferation; Neoplasm Staging; 0303 health sciences; Nasopharyngeal Carcinoma; Research; Cell Cycle; PTEN Phosphohydrolase; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; miR-141; Gene Expression Regulation, Neoplastic; MicroRNAs; AKT pathway; Gene Knockdown Techniques; Female; Feedback loop; Neoplasm Grading; BRD7; Proto-Oncogene Proteins c-akt

miR-141 is up-regulated and plays crucial roles in nasopharyngeal carcinoma (NPC). However, the molecular mechanism underlying the dysregulation of miR-141 is still obscure.Thus, the ChIP-PCR was performed to identify the c-Myc-binding sites in miR-141 and BRD7. qRT-PCR, western blot and immunohistochemistry assays were used to detect the expression of miR-141 and its up/down stream molecules. The rescue experiments on the c-Myc/miR-141 axis were performed in vitro and in vivo.Our results showed that the levels of mature miR-141, pre-miR-141 and pri-miR-141 were downregulated in c-Myc knockdown NPC cells. Meanwhile, c-Myc transactivates the expression of miR-141 by binding its promoter region. Moreover, BRD7 was identified as a co-factor of c-Myc to negatively regulate the activation of c-Myc/miR-141 axis, as well as a direct target of c-Myc. Moreover, restoration of miR-141 in c-Myc knockdown NPC cells notably rescued the effect of c-Myc on cell proliferation and tumor growth, as well as the blocking of PTEN/AKT pathway. Additionally, the expression of c-Myc was positively correlated with that of miR-141 and the clinical stages of NPC patients and negatively associated with the expression of BRD7. Our findings demonstrated that BRD7 expression and c-Myc activation forms a negative feedback loop to control the cell proliferation and tumor growth by targeting miR-141.These observations provide new mechanistic insights into the dysregulation of miR-141 expression and a promising therapeutic option for NPC.