title: Progression of mouse skin carcinogenesis is associated with the orchestrated deregulation of mir-200 family members, mir-205 and their common targets.
abstract: MicroRNAs are small, non-coding RNAs which regulate post-transcriptionally hundreds of target mRNAs. Given that their expression is deregulated in several cancer types, they represent potential diagnostic, prognostic, and predictive biomarkers, as well as next-generation therapeutic targets. Nevertheless, the involvement of miRNAs in non-melanoma skin cancer, a cancer type with increasing prevalence, is not extensively studied, and their comprehensive characterization as regard to the initiation, promotion, and progression stages is missing. To this end, we exploited a well-established multistage mouse skin carcinogenesis model in order to identify miRNAs consistently implicated in different stages of skin carcinogenesis. The cell lines comprising this model were subjected to miRNA expression profiling using microarrays, followed by bioinformatics analysis and validation with Q-PCR, as well as treatment with miRNA modulators. We showed that among all deregulated miRNAs in our system, only a functionally coherent group consisting of the miR-200 family members and miR-205-5p displays a pattern of progressive co-downregulation from the early toward the most aggressive stages of carcinogenesis. Their overlapping, co-regulated putative targets are potentially inter-associated and, of these, the EMT-related Rap1a is overexpressed toward aggressive stages. Ectopic expression of miR-205-5p in spindle cancer cells reduces Rap1a, mitigates cell invasiveness, decreases proliferation, and delays tumor onset. We conclude that deregulation of this miRNA group is primarily associated with aggressive phenotypes of skin cancer cells. Restoration of the miR-205-5p member of this group in spindle cells reduces the expression of critical, co-regulated targets that favor cancer progression, thus reversing the EMT characteristics. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: Elena
authors.initials: E
authors.lastname: Skourti
authors.affiliation: Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: Stella
authors.initials: S
authors.lastname: Logotheti
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Athens, Greece.
authors.forename: Christos K
authors.initials: CK
authors.lastname: Kontos
authors.affiliation: Computational Biology and Medicine, Centre of Systems Biology, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
authors.forename: Athanasia
authors.initials: A
authors.lastname: Pavlopoulou
authors.affiliation: Computational Biology and Medicine, Centre of Systems Biology, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
authors.forename: Paraskevi T
authors.initials: PT
authors.lastname: Dimoragka
authors.affiliation: Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Athens, Greece.
authors.forename: Ioannis P
authors.initials: IP
authors.lastname: Trougakos
authors.affiliation: Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Gorgoulis
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Athens, Greece.
authors.forename: Andreas
authors.initials: A
authors.lastname: Scorilas
authors.affiliation: Computational Biology and Medicine, Centre of Systems Biology, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Michalopoulos
authors.affiliation: Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Zoumpourlis
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D015536:Down-Regulation; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D020827:rap1 GTP-Binding Proteins / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D020827:rap1 GTP-Binding Proteins; C533896:MIRN200 microRNA, human; C534425:MIR205, human; C430803:RAP1A protein, human
keywords: Rap1a; miR-200; miR-205; mouse skin carcinogenesis; stages of cancer; tumor progression