title: A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis.
abstract: Most p53 mutations in human cancers are missense mutations resulting in a full-length mutant p53 protein. Besides losing tumor suppressor activity, some hotspot p53 mutants gain oncogenic functions. This effect is mediated in part, through gene expression changes due to inhibition of p63 and p73 by mutant p53 at their target gene promoters. Here, we report that the tumor suppressor microRNA let-7i is downregulated by mutant p53 in multiple cell lines expressing endogenous mutant p53. In breast cancer patients, significantly decreased let-7i levels were associated with missense mutations in p53. Chromatin immunoprecipitation and promoter luciferase assays established let-7i as a transcriptional target of mutant p53 through p63. Introduction of let-7i to mutant p53 cells significantly inhibited migration, invasion and metastasis by repressing a network of oncogenes including E2F5, LIN28B, MYC and NRAS. Our findings demonstrate that repression of let-7i expression by mutant p53 has a key role in enhancing migration, invasion and metastasis.
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Subramanian
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: P
authors.initials: P
authors.lastname: Francis
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bilke
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: X L
authors.initials: XL
authors.lastname: Li
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: T
authors.initials: T
authors.lastname: Hara
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Howard University, Washington, DC, USA.
authors.forename: X
authors.initials: X
authors.lastname: Lu
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Jones
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Walker
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Pineda
authors.affiliation: Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: L
authors.initials: L
authors.lastname: Varanasi
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Martinez
authors.affiliation: Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Luo
authors.affiliation: Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ambs
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Howard University, Washington, DC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Wakefield
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Meltzer
authors.affiliation: Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Lal
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D005260:Female; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics*; D020125:Mutation, Missense; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D034741:RNA, Small Interfering; C495901:TP53 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C487931:mirnlet7 microRNA, human