Han Han, Chen Yuxing, Cheng Li, Prochownik Edward V, Li Youjun
College of Life Sciences, Medical Research Institute, Wuhan University, Wuhan 430072, China.
Division of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC and The Department of Microbiology and Molecular Genetics, The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224, USA.
Oncotarget. 2016 Mar 29;7(13):16409-19. doi: 10.18632/oncotarget.7653.
c-Myc (Myc) is one of the most frequently dysregulated oncogenic transcription factors in human cancer. By functionally screening a microRNA (miR) library, we identified miR-206 as being a synthetic lethal in Myc over-expressing human cancer cells. miR-206 inhibited MAP3K13, which resulted in Myc protein de-stabilization, and an inhibition of anchorage-independent growth and in vivo tumorigenesis by Myc over-expressing human cancer cells. Eliminating MAP3K13 by shRNA recapitulated the effects caused by miR-206, thus supporting the idea that miR-206's effect on Myc was mediated through MAP3K13. Conversely, enforced expression of MAP3K13 stabilized Myc by promoting its N-terminal phosphorylation and enhancing its transcriptional activity. Gene expression analyses of breast cancers expressing high levels of Myc indicated that low miR-206 expression and high MAP3K13 expression correlated with poor patient survival. The critical link between miR-206 and MAP3K13 in the development of Myc over-expressing human cancers suggests potential points of therapeutic intervention for this molecular sub-category.
c-Myc（Myc）是人类癌症中最常失调的致癌转录因子之一。通过对微小RNA（miR）文库进行功能筛选，我们确定miR-206在Myc过表达的人类癌细胞中具有合成致死作用。miR-206抑制丝裂原活化蛋白激酶激酶激酶13（MAP3K13），导致Myc蛋白不稳定，并抑制Myc过表达的人类癌细胞的非锚定依赖性生长和体内肿瘤发生。通过短发夹RNA（shRNA）消除MAP3K13可重现miR-206所引起的效应，从而支持miR-206对Myc的作用是通过MAP3K13介导的这一观点。相反，MAP3K13的强制表达通过促进其N端磷酸化并增强其转录活性来稳定Myc。对高表达Myc的乳腺癌进行基因表达分析表明，低miR-206表达和高MAP3K13表达与患者生存不良相关。miR-206与MAP3K13在Myc过表达的人类癌症发生发展中的关键联系提示了针对这一分子亚类的潜在治疗干预点。
