PLoS One. 2014 Mar 13;9(3):e90524. doi: 10.1371/journal.pone.0090524. eCollection 2014.

MicroRNA-Dependent Regulation of Transcription in Non-Small Cell Lung Cancer.

Molina-Pinelo S1, Gutiérrez G2, Pastor MD1, Hergueta M3, Moreno-Bueno G3, García-Carbonero R4, Nogal A5, Suárez R1, Salinas A1, Pozo-Rodríguez F6,Lopez-Rios F7, Agulló-Ortuño MT8, Ferrer I1, Perpiñá A9, Palacios J10, Carnero A11, Paz-Ares L4.

Author information

• 1Molecular Oncology and New Therapies Group. Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.
• 2Genetic Department, Universidad de Sevilla, Seville, Spain.
• 3Biochemistry Department, Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, Madrid, Spain; IdiPAZ (Instituto de Investigación Sanitaria La Paz) & Fundación MD Anderson International, Madrid Spain.
• 4Molecular Oncology and New Therapies Group. Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain; Medical Oncology Department, Hospital Universitario Virgen del Rocio, Sevilla, Spain.
• 5Molecular Oncology and New Therapies Group. Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Porto, Portugal.
• 6Service of Neumology, Hospital 12 de Octubre, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain.
• 7Pathology Department, Laboratorio de Dianas Terapéuticas, Centro Integral Oncológico Clara Campal, Madrid, Spain.
• 8Service of Oncology, Instituto de Investigación Sanitaria i+12, Hospital Doce de Octubre, Madrid, Spain.
• 9Service of Neumology, Hospital Severo Ochoa, Madrid, Spain.
• 10Department of Pathology, Hospital Universitario Ramón y Cajal, Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), Madrid, Spain.
• 11Molecular Biology of Cancer Group, Instituto de Biomedicina de Sevilla (IBIS)/(HUVR, CSIC, Universidad de Sevilla), Seville, Spain.

Abstract

Squamous cell lung cancer (SCC) and adenocarcinoma are the most common histological subtypes of non-small cell lung cancer (NSCLC), and have been traditionally managed in the clinic as a single entity. Increasing evidence, however, illustrates the biological diversity of these two histological subgroups of lung cancer, and supports the need to improve our understanding of the molecular basis beyond the different phenotypes if we aim to develop more specific and individualized targeted therapy. The purpose of this study was to identify microRNA (miRNA)-dependent transcriptional regulation differences between SCC and adenocarcinoma histological lung cancer subtypes. In this work, paired miRNA (667 miRNAs by TaqMan Low Density Arrays (TLDA)) and mRNA profiling (Whole Genome 44 K array G112A, Agilent) was performed in tumor samples of 44 NSCLC patients. Nine miRNAs and 56 mRNAs were found to be differentially expressed in SCC versus adenocarcinoma samples. Eleven of these 56 mRNA were predicted as targets of the miRNAs identified to be differently expressed in these two histological conditions. Of them, 6 miRNAs (miR-149, miR-205, miR-375, miR-378, miR-422a and miR-708) and 9 target genes (CEACAM6, CGN, CLDN3, ABCC3, MLPH, ACSL5, TMEM45B, MUC1) were validated by quantitative PCR in an independent cohort of 41 lung cancer patients. Furthermore, the inverse correlation between mRNAs and microRNAs expression was also validated. These results suggest miRNA-dependent transcriptional regulation differences play an important role in determining key hallmarks of NSCLC, and may provide new biomarkers for personalized treatment strategies.