Integrative transcriptome analysis identifies deregulated microRNA-transcription factor networks in lung adenocarcinoma

// Naiara C. Cinegaglia 1 , Sonia Cristina S. Andrade 2,3 , Tomas Tokar 13 , Maisa Pinheiro 4 , Fabio E. Severino 1 , Rogerio A. Oliveira 5 , Erica N. Hasimoto 1 , Daniele C. Cataneo 1 , Antonio J.M. Cataneo 1 , Julio Defaveri 6 , Cristiano P. Souza 1,7 , Marcia M.C. Marques 7,8 , Robson F. Carvalho 9 , Luiz L. Coutinho 2 , Jefferson L. Gross 10 , Silvia R. Rogatto 10,11 , Wan L. Lam 12 , Igor Jurisica 13,14 and Patricia P. Reis 1,15 1 Department of Surgery and Orthopedics, Sao Paulo State University (UNESP), Botucatu, SP, Brazil 2 Department of Animal Biotechnology, University of Sao Paulo (USP), Piracicaba, SP, Brazil 3 Institute of Biosciences, University of Sao Paulo (USP), Sao Paulo, SP, Brazil 4 Department of Genetics, Sao Paulo State University (UNESP), Botucatu, SP, Brazil 5 Department of Biostatistics, Sao Paulo State University (UNESP), Botucatu, SP, Brazil 6 Department of Pathology, Sao 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, Sao Paulo State University (UNESP), Botucatu, SP, Brazil 10 International Center of Research and Training (CIPE), A. C. Camargo Cancer Center, Sao Paulo, SP, Brazil 11 Department of Urology, Sao 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, Sao Paulo State University (UNESP), Botucatu, SP, Brazil Correspondence to: 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 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.