title: Suppression of MicroRNA 200 Family Expression by Oncogenic KRAS Activation Promotes Cell Survival and Epithelial-Mesenchymal Transition in KRAS-Driven Cancer.
abstract: Oncogenic KRAS contributes to malignant transformation, antiapoptosis, and metastasis in multiple human cancers, such as lung, colon, and pancreatic cancers and melanoma. MicroRNAs (miRNAs) are endogenous 18- to 25-nucleotide noncoding small RNAs that regulate gene expression in a sequence-specific manner via the degradation of target mRNAs or inhibition of protein translation. In the present study, using array-based miRNA profiling in IMR90 and MCF10A cells expressing oncogenic KRAS, we identified that the expression of the microRNA 200 (mir-200) family was suppressed by KRAS activation and that this suppression was mediated by the transcription factors JUN and SP1 in addition to ZEB1. Restoration of mir-200 expression compromised KRAS-induced cellular transformation in vitro and tumor formation in vivo In addition, we found that enforced expression of mir-200 abrogated KRAS-induced resistance to apoptosis by directly targeting the antiapoptotic gene BCL2 Finally, mir-200 was able to antagonize the epithelial-mesenchymal transition (EMT) driven by mutant KRAS. Collectively, our results suggest that repression of endogenous mir-200 expression is one of the important cellular responses to KRAS activation during tumor initiation and progression.
authors.affiliation: Center for Stem Cell Biology and Tissue Engineering, Department of Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China zhongxm23@mail.sysu.edu.cn linzhang@mail.med.upenn.edu.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Center for Research on Reproduction & Women's Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Center for Research on Reproduction & Women's Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Shen
authors.affiliation: Center for Research on Reproduction & Women's Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Center for Stem Cell Biology and Tissue Engineering, Department of Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Xiong
authors.affiliation: Center for Research on Reproduction & Women's Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Youyou
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Research on Reproduction & Women's Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Xinhong
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Janos L
authors.initials: JL
authors.lastname: Tanyi
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Kathleen T
authors.initials: KT
authors.lastname: Montone
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Chen
authors.affiliation: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
authors.forename: Congjian
authors.initials: C
authors.lastname: Xu
authors.affiliation: Center for Stem Cell Biology and Tissue Engineering, Department of Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Andy P
authors.initials: AP
authors.lastname: Xiang
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Qihong
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.affiliation: Center for Research on Reproduction & Women's Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA zhongxm23@mail.sysu.edu.cn linzhang@mail.med.upenn.edu.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D009857:Oncogenes; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D016329:Sp1 Transcription Factor
chemical_list: C117307:KRAS protein, human; D035683:MicroRNAs; D016755:Proto-Oncogene Proteins c-jun; D016329:Sp1 Transcription Factor; D016283:Proto-Oncogene Proteins p21(ras)