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

Abstract

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.

Homeobox D9 drives the malignant phenotypes and enhances the Programmed death ligand-1 expression in non-small cell lung cancer cells via binding to Angiopoietin-2 promoter

“…Previously clinic research suggested that HOXD9 level was highly expressed in the cancerous tissues from NSCLC patients [15]. This means that high HOXD9 expression might be associated with the development of NSCLC.…”

“…Moreover, HOXD9 silencing induced apoptosis of tumor cells by activating the p53 pathway [9]. Recently, HOXD9 was found to be highly expressed in tumor samples from NSCLC patients and had a significant negative correlation with patients' overall survival [15]. Therefore, HOXD9 is proposed to be a valuable prognostic biomarker for NSCLC.…”

Identification of miR-151a as a novel endogenous control for small extracellular vesicle cargo normalization in human cancer

“…These cell lines were purchased from the ATCC (Manassas, VA, USA) or ECACC (Sigma-Aldrich, Spain) and authenticated by the Genomics Department of the Alberto Sols Biomedical Research Institute (iiBm) CSIC-UAM, through microsatellite analysis of speci c loci within the Human Genome using the GenePrint 10 kit (Promega, USA) (Supplementary Table 1). Cisplatin (CDDP) resistant variants H23R, OVCAR-3R and A2780R were established previously by our group (41,(71)(72)(73)(74). Carboplatin (CBDCA) resistant subtypes H23 and A2780 were established by exposing cells to increasing doses of carboplatin as described in the literature (74), obtaining a nal CBDCA concentration of 2.5 and 1.25 µg/mL, respectively (Supplementary Figure 1).…”

Polygonum cuspidatum Extract (Pc-Ex) Containing Emodin Suppresses Lung Cancer-Induced Cachexia by Suppressing TCF4/TWIST1 Complex-Induced PTHrP Expression

“…TCF4 exerts oncogenic effects by promoting the proliferation, invasion, and chemoresistance of melanoma, lung, colorectal, and breast cancers [ 16 , 22 , 23 , 24 , 25 , 26 ]. In contrast, several studies have demonstrated that TCF4 suppresses the growth and progression, which are associated with poor prognosis, of non-small cell lung carcinoma and colorectal cancer [ 27 , 28 , 29 , 30 ]. TWIST1, a bHLH-domain-containing transcription factor, is reported to promote epithelial-to-mesenchymal transition (EMT), which increases the invasiveness and metastasis of epithelial cancers [ 31 ].…”