PT  - JOURNAL ARTICLE
AU  - Olga Pernía
AU  - Ana Sastre-Perona
AU  - Carlos Rodriguez-Antolín
AU  - Alvaro García-Guede
AU  - María Palomares-Bralo
AU  - Rocío Rosas
AU  - Darío Sanchez-Cabrero
AU  - Carmen Rodriguez
AU  - Rubén Martín-Arenas
AU  - Verónica Pulido
AU  - Javier de Castro
AU  - Pilar Santisteban
AU  - Olga Vera
AU  - Inmaculada Ibáñez de Cáceres
TI  - A novel role for the tumor suppressor gene <em>ITF2</em> in lung tumorigenesis through the action of Wnt signaling pathway
AID  - 10.1101/517169
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 517169
4099  - http://biorxiv.org/content/early/2019/01/10/517169.short
4100  - http://biorxiv.org/content/early/2019/01/10/517169.full
AB  - Despite often leading to a platinum resistance, platinum-based chemotherapy continues to be the standard treatment for non-small cell lung cancer (NSCLC) and ovarian cancer. In this study, we used array-CGH and qRT-PCR methodologies to identify and validate cytogenetic alterations that arise after cisplatin treatment in four paired cisplatin-sensitive/resistant cell lines. We found the presence of a common deletion of the gene ITF2 in cisplatin-resistant cell lines. Our translational approach included the expression analysis in a total of 35 lung and ovarian primary tumors, showing a frequent downregulation of ITF2. Whole transcriptome sequencing (RNA-seq) and Wnt-pathway analysis in a subgroup of NSCLC patients identified four genes with a potential role in the development of this malignancy. Further functional assays overexpressing ITF2 in NSCLC cisplatin-resistant cells suggest the regulation of HOXD9 by the Wnt pathway and its implication on NSCLC progression.One-sentence summary Our study identifies Wnt-signaling pathway as a molecular mechanism behind the development of platinum-resistance through ITF2 action; as well as to present two potential therapeutic targets for further studies, ITF2 and HOXD9.Abbreviations used in the manuscriptHULPHospital Universitario La PazTCF4Transcription Factor 4CDDPcisplatinqRT-PCRquantitative real-time PCRqMSPquantitative methylation-specific PCRNSCLCnon-small cell lung cancerATTadjacent tumor tissuesAbbreviationsATTAdjacent Tumor TissuesCGHComparative genomic hybridizationNSCLCNon-Small Cell Lung CancerNLMNormal lung meanTCF4transcription factor 4HOXD9RIOX1, Ribosomal Oxygenase 1