title: MiR-194, commonly repressed in colorectal cancer, suppresses tumor growth by regulating the MAP4K4/c-Jun/MDM2 signaling pathway.
abstract: Tumor growth cascade is a complicated and multistep process with numerous obstacles. Until recently, evidences have shown the involvement of microRNAs (miRNAs) in tumorigenesis and tumor progression of various cancers, including colorectal cancer (CRC). In this study, we explored the role of miR-194 and its downstream pathway in CRC. We acquired data through miRNA microarray profiles, showing that the expression of miR-194 was significantly suppressed in CRC tissues compared with corresponding noncancerous tissues. Decreased miR-194 expression was obviously associated with tumor size and tumor differentiation, as well as TNM stage. Both Kaplan-Meier and multivariate survival analysis showed that downregulated miR-194 was associated with overall survival. Moreover, functional assays indicated that overexpression of miR-194 in CRC cell lines inhibited cell proliferation both in vitro and in vivo. In addition, using dual-luciferase reporter gene assay, we found MAP4K4 was the direct target of miR-194. Silencing of MAP4K4 resulted in similar biological behavior changes to that of overexpression of miR-194. We also observed through Human Gene Expression Array that MDM2 was one of the downstream targets of MAP4K4. Knockdown of MAP4K4 downregulated MDM2 expression through transcription factor c-Jun binding to the -1063 to -1057 bp of the promoter. These results suggest that miR-194, regulating the MAP4K4/c-Jun/MDM2 signaling pathway, might act as a tumor suppressor and serve as a novel target for CRC prevention and therapy.
authors.affiliation: a Department of Gastroenterological Surgery ; Peking University People's Hospital ; Beijing , PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Zhan-long
authors.initials: ZL
authors.lastname: Shen
authors.forename: Zhi-dong
authors.initials: ZD
authors.lastname: Gao
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.forename: Chun-you
authors.initials: CY
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Ji-zhun
authors.initials: JZ
authors.lastname: Zhang
authors.forename: Yi-chao
authors.initials: YC
authors.lastname: Yan
authors.forename: Chao
authors.initials: C
authors.lastname: Shen
authors.forename: Ke-wei
authors.initials: KW
authors.lastname: Jiang
authors.forename: Ying-jiang
authors.initials: YJ
authors.lastname: Ye
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015999:Multivariate Analysis; D009368:Neoplasm Transplantation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction
chemical_list: D020413:3' Untranslated Regions; D047908:Intracellular Signaling Peptides and Proteins; C554846:MIRN194 microRNA, human; D035683:MicroRNAs; D016755:Proto-Oncogene Proteins c-jun; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C117090:MAP4K4 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: MAP4K4; MDM2; apoptosis; c-Jun; colorectal cancer; miR-194; proliferation