Preprint Article Version 1 This version is not peer-reviewed

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

Version 1 : Received: 27 February 2020 / Approved: 28 February 2020 / Online: 28 February 2020 (11:58:28 CET)

A peer-reviewed article of this Preprint also exists.

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.; Castro, J.; Vera, O.; Cáceres, I.I. A Novel Role for the Tumor Suppressor Gene ITF2 in Tumorigenesis and Chemotherapy Response. Cancers 2020, 12, 786. 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.; Castro, J.; Vera, O.; Cáceres, I.I. A Novel Role for the Tumor Suppressor Gene ITF2 in Tumorigenesis and Chemotherapy Response. Cancers 2020, 12, 786.

Journal reference: Cancers 2020, 12, 786
DOI: 10.3390/cancers12040786

Abstract

Despite often leading to platinum resistance, platinum-based chemotherapy continues to be the standard treatment for many epithelial tumors. In this study we analyze and validated the cytogenetic alterations that arise after treatment in four lung and ovarian paired cisplatin-sensitive/resistant cell lines by 1-million 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. 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-sensitizes tumor cells to platinum and recovers 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 NSCLC patients with lower expression of HOXD9 have a better overall survival rate. We define 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.

Subject Areas

ITF2_TCF4; chemotheraoy resistance; NSCLC; HOXD9; Wnt pathway

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