title: Integrative transcriptome analysis identifies deregulated microRNA-transcription factor networks in lung adenocarcinoma.
abstract: Herein, we aimed at identifying global transcriptome microRNA (miRNA) changes and miRNA target genes in lung adenocarcinoma. Samples were selected as training (N = 24) and independent validation (N = 34) sets. Tissues were microdissected to obtain >90% tumor or normal lung cells, subjected to miRNA transcriptome sequencing and TaqMan quantitative PCR validation. We further integrated our data with published miRNA and mRNA expression datasets across 1,491 lung adenocarcinoma and 455 normal lung samples. We identified known and novel, significantly over- and under-expressed (p ≤ 0.01 and FDR≤0.1) miRNAs in lung adenocarcinoma compared to normal lung tissue: let-7a, miR-10a, miR-15b, miR-23b, miR-26a, miR-26b, miR-29a, miR-30e, miR-99a, miR-146b, miR-181b, miR-181c, miR-421, miR-181a, miR-574 and miR-1247. Validated miRNAs included let-7a-2, let-7a-3, miR-15b, miR-21, miR-155 and miR-200b; higher levels of miR-21 expression were associated with lower patient survival (p = 0.042). We identified a regulatory network including miR-15b and miR-155, and transcription factors with prognostic value in lung cancer. Our findings may contribute to the development of treatment strategies in lung adenocarcinoma.
authors.affiliation: Department of Surgery and Orthopedics, São Paulo State University (UNESP), Botucatu, SP, Brazil.
authors.forename: Naiara C
authors.initials: NC
authors.lastname: Cinegaglia
authors.affiliation: Department of Animal Biotechnology, University of São Paulo (USP), Piracicaba, SP, Brazil.|Institute of Biosciences, University of São Paulo (USP), São Paulo, SP, Brazil.
authors.forename: Sonia Cristina S
authors.initials: SC
authors.lastname: Andrade
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Tomas
authors.initials: T
authors.lastname: Tokar
authors.affiliation: Department of Genetics, São Paulo State University (UNESP), Botucatu, SP, Brazil.
authors.forename: Maísa
authors.initials: M
authors.lastname: Pinheiro
authors.affiliation: Department of Surgery and Orthopedics, São Paulo State University (UNESP), Botucatu, SP, Brazil.
authors.forename: Fábio E
authors.initials: FE
authors.lastname: Severino
authors.affiliation: Department of Biostatistics, São Paulo State University (UNESP), Botucatu, SP, Brazil.
authors.forename: Rogério A
authors.initials: RA
authors.lastname: Oliveira
authors.affiliation: Department of Surgery and Orthopedics, São Paulo State University (UNESP), Botucatu, SP, Brazil.
authors.forename: Erica N
authors.initials: EN
authors.lastname: Hasimoto
authors.affiliation: Department of Surgery and Orthopedics, São Paulo State University (UNESP), Botucatu, SP, Brazil.
authors.forename: Daniele C
authors.initials: DC
authors.lastname: Cataneo
authors.affiliation: Department of Surgery and Orthopedics, São Paulo State University (UNESP), Botucatu, SP, Brazil.
authors.forename: Antônio J M
authors.initials: AJ
authors.lastname: Cataneo
authors.affiliation: Department of Pathology, São Paulo State University (UNESP), Botucatu, SP, Brazil.
authors.forename: Júlio
authors.initials: J
authors.lastname: Defaveri
authors.affiliation: Department of Surgery and Orthopedics, São Paulo State University (UNESP), Botucatu, SP, Brazil.|Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil.
authors.forename: Cristiano P
authors.initials: CP
authors.lastname: Souza
authors.affiliation: Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil.|Barretos School of Health Sciences, Barretos, SP, Brazil.
authors.forename: Márcia M C
authors.initials: MM
authors.lastname: Marques
authors.affiliation: Department of Morphology, São Paulo State University (UNESP), Botucatu, SP, Brazil.
authors.forename: Robson F
authors.initials: RF
authors.lastname: Carvalho
authors.affiliation: Department of Animal Biotechnology, University of São Paulo (USP), Piracicaba, SP, Brazil.
authors.forename: Luiz L
authors.initials: LL
authors.lastname: Coutinho
authors.affiliation: International Center of Research and Training (CIPE), A. C. Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Jefferson L
authors.initials: JL
authors.lastname: Gross
authors.affiliation: International Center of Research and Training (CIPE), A. C. Camargo Cancer Center, São Paulo, SP, Brazil.|Department of Urology, São Paulo State University, UNESP, Botucatu, SP, Brazil.
authors.forename: Silvia R
authors.initials: SR
authors.lastname: Rogatto
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Igor
authors.initials: I
authors.lastname: Jurisica
authors.affiliation: Department of Surgery and Orthopedics, São Paulo State University (UNESP), Botucatu, SP, Brazil.|Experimental Research Unity (UNIPEX), Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil.
authors.forename: Patricia P
authors.initials: PP
authors.lastname: Reis
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome
chemical_list: D035683:MicroRNAs; D014157:Transcription Factors
keywords: lung adenocarcinoma; microRNAs; molecular targets; transcription factor networks; transcriptome sequencing