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Article

A Novel Role for the Tumor Suppressor Gene ITF2 in Tumorigenesis and Chemotherapy Response

1
Epigenetics Laboratory, INGEMM, Hospital La PAZ. 28046 Madrid, Spain
2
Experimental Therapies and novel biomarkers in cancer IdiPAZ. 28046 Madrid, Spain
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Instituto de Investigaciones Biomedicas CSIC/UAM. 28029 Madrid, Spain
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Ciber de Enfermedades Raras (CIBERER). Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
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Laboratorio de Genómica Estructural y Funcional, INGEMM. IdiPAZ. 28046 Madrid, Spain
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Gynaecologic Oncology Unit, La Paz University Hospital, 28046 Madrid, Spain
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Ciber de Cáncer (CIBERONC) Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
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Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
*
Authors to whom correspondence should be addressed.
Both authors contributed equally to this work.
Cancers 2020, 12(4), 786; https://doi.org/10.3390/cancers12040786
Received: 27 February 2020 / Revised: 22 March 2020 / Accepted: 24 March 2020 / Published: 26 March 2020
(This article belongs to the Special Issue Non-small Cell Lung Cancer--Tumor Biology)
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. View Full-Text
Keywords: ITF2-TCF4; chemotherapy resistance; NSCLC; HOXD9; Wnt pathway ITF2-TCF4; chemotherapy resistance; NSCLC; HOXD9; Wnt pathway
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MDPI and ACS Style

Pernía, O.; Sastre-Perona, A.; Rodriguez-Antolín, C.; García-Guede, A.; Palomares-Bralo, M.; Rosas, R.; Sanchez-Cabrero, D.; Cruz, P.; Rodriguez, C.; Diestro, M.; Martín-Arenas, R.; Pulido, V.; Santisteban, P.; de Castro, J.; Vera, O.; Ibáñez de Cáceres, I. A Novel Role for the Tumor Suppressor Gene ITF2 in Tumorigenesis and Chemotherapy Response. Cancers 2020, 12, 786. https://doi.org/10.3390/cancers12040786

AMA Style

Pernía O, Sastre-Perona A, Rodriguez-Antolín C, García-Guede A, Palomares-Bralo M, Rosas R, Sanchez-Cabrero D, Cruz P, Rodriguez C, Diestro M, Martín-Arenas R, Pulido V, Santisteban P, de Castro J, Vera O, Ibáñez de Cáceres I. A Novel Role for the Tumor Suppressor Gene ITF2 in Tumorigenesis and Chemotherapy Response. Cancers. 2020; 12(4):786. https://doi.org/10.3390/cancers12040786

Chicago/Turabian Style

Pernía, Olga, Ana Sastre-Perona, Carlos Rodriguez-Antolín, Alvaro García-Guede, María Palomares-Bralo, Rocío Rosas, Darío Sanchez-Cabrero, Patricia Cruz, Carmen Rodriguez, MDolores Diestro, Rubén Martín-Arenas, Verónica Pulido, Pilar Santisteban, Javier de Castro, Olga Vera, and Inmaculada Ibáñez de Cáceres. 2020. "A Novel Role for the Tumor Suppressor Gene ITF2 in Tumorigenesis and Chemotherapy Response" Cancers 12, no. 4: 786. https://doi.org/10.3390/cancers12040786

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