title: microRNA-206 impairs c-Myc-driven cancer in a synthetic lethal manner by directly inhibiting MAP3K13.
abstract: 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.
authors.affiliation: College of Life Sciences, Medical Research Institute, Wuhan University, Wuhan 430072, China.
authors.forename: Han
authors.initials: H
authors.lastname: Han
authors.affiliation: College of Life Sciences, Medical Research Institute, Wuhan University, Wuhan 430072, China.
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: College of Life Sciences, Medical Research Institute, Wuhan University, Wuhan 430072, China.
authors.forename: Li
authors.initials: L
authors.lastname: Cheng
authors.affiliation: 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.
authors.forename: Edward V
authors.initials: EV
authors.lastname: Prochownik
authors.affiliation: College of Life Sciences, Medical Research Institute, Wuhan University, Wuhan 430072, China.
authors.forename: Youjun
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D020930:MAP Kinase Kinase Kinases / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D014183:Transplantation, Heterologous
chemical_list: C546087:MIRN206 microRNA, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D020930:MAP Kinase Kinase Kinases; C109162:MAP3K13 protein, human
keywords: MAP3K13; Myc; breast cancer; microRNA