A novel role for the tumor suppressor gene itf2 in tumorigenesis and chemotherapy response

Despite often leading to platinum resistance, platinum-based chemotherapy continues to be the standard treatment for many epithelial tumors. In this study we analyzed and validated the cytogenetic alterations that arise after treatment in four lung and ovarian paired cisplatin-sensitive/resistant ce...

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Bibliographic Details
Authors: Pernía, Olga, Sastre-Perona, Ana, Rodriguez-Antolín, Carlos, García-Guede, Alvaro, Palomares-Bralo, María, Rosas, Rocío, Sanchez-Cabrero, Darío, Cruz, Patricia, Rodriguez, Carmen, Diestro Tejada, María Dolores, Martín-Arenas, Rubén, Pulido, Verónica, Santisteban, Pilar, de Castro, Javier, Vera, Olga, Ibáñez de Cáceres, Inmaculada
Format: article
Publication Date:2020
Country:España
Institution:Universidad Autónoma de Madrid
Repository:Biblos-e Archivo. Repositorio Institucional de la UAM
Language:English
OAI Identifier:oai:repositorio.uam.es:10486/693021
Online Access:http://hdl.handle.net/10486/693021
https://dx.doi.org/10.3390/cancers12040786
Access Level:Open access
Keyword:Chemotherapy resistance
HOXD9
ITF2-TCF4
NSCLC
Wnt pathway
Medicina
Description
Summary:Despite often leading to platinum resistance, platinum-based chemotherapy continues to be the standard treatment for many epithelial tumors. In this study we analyzed and validated the cytogenetic alterations that arise after treatment in four lung and ovarian paired cisplatin-sensitive/resistant cell lines by 1-million microarray-based comparative genomic hybridization (array-CGH) and qRT-PCR methodologies. RNA-sequencing, functional transfection assays, and gene-pathway activity analysis were used to identify genes with a potential role in the development of this malignancy. The results were further explored in 55 lung and ovarian primary tumors and control samples, and in two extensive in silico databases. Long-term cell exposure to platinum induces the frequent deletion of ITF2 gene. Its expression re-sensitized tumor cells to platinum and recovered the levels of Wnt/β-catenin transcriptional activity. ITF2 expression was also frequently downregulated in epithelial tumors, predicting a worse overall survival. We also identified an inverse correlation between ITF2 and HOXD9 expression, revealing that Non-small cell lung cancer (NSCLC) patients with lower expression of HOXD9 had a better overall survival rate. We defined the implication of ITF2 as a molecular mechanism behind the development of cisplatin resistance probably through the activation of the Wnt-signaling pathway. This data highlights the possible role of ITF2 and HOXD9 as novel therapeutic targets for platinum resistant tumors.

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