Integrative transcriptome analysis identifies deregulated microRNA-transcription factor networks in lung adenocarcinoma
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Naiara C. Cinegaglia1, Sonia Cristina S. Andrade2,3, Tomas Tokar13, Maísa Pinheiro4, Fábio E. Severino1, Rogério A. Oliveira5, Erica N. Hasimoto1, Daniele C. Cataneo1, Antônio J.M. Cataneo1, Júlio Defaveri6, Cristiano P. Souza1,7, Márcia M.C. Marques7,8, Robson F. Carvalho9, Luiz L. Coutinho2, Jefferson L. Gross10, Silvia R. Rogatto10,11, Wan L. Lam12, Igor Jurisica13,14 and Patricia P. Reis1,15
1 Department of Surgery and Orthopedics, São Paulo State University (UNESP), Botucatu, SP, Brazil
2 Department of Animal Biotechnology, University of São Paulo (USP), Piracicaba, SP, Brazil
3 Institute of Biosciences, University of São Paulo (USP), São Paulo, SP, Brazil
4 Department of Genetics, São Paulo State University (UNESP), Botucatu, SP, Brazil
5 Department of Biostatistics, São Paulo State University (UNESP), Botucatu, SP, Brazil
6 Department of Pathology, São Paulo State University (UNESP), Botucatu, SP, Brazil
7 Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
8 Barretos School of Health Sciences, Barretos, SP, Brazil
9 Department of Morphology, São Paulo State University (UNESP), Botucatu, SP, Brazil
10 International Center of Research and Training (CIPE), A. C. Camargo Cancer Center, São Paulo, SP, Brazil
11 Department of Urology, São Paulo State University, UNESP, Botucatu, SP, Brazil
12 Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada
13 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
14 Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, ON, Canada
15 Experimental Research Unity (UNIPEX), Faculty of Medicine, São Paulo State University (UNESP), Botucatu, SP, Brazil
Patricia P. Reis, email:
Igor Jurisica, email:
Keywords: lung adenocarcinoma, transcriptome sequencing, microRNAs, transcription factor networks, molecular targets
Received: October 13, 2015 Accepted: March 28, 2016 Published: April 12, 2016
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.
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