CDC25A(Q110del): a novel cell division cycle 25A isoform aberrantly expressed in non-small cell lung cancer.

Abstract

Lung cancer remains number one cause of cancer related deaths worldwide. Cell cycle deregulation plays a major role in the pathogenesis of Non-Small Cell Lung Cancer (NSCLC). CDC25A represents a critical cell cycle regulator that enhances cell cycle progression. In this study we aimed to investigate the role of a novel CDC25A transcriptional variant, CDC25A(Q110del), on the regulation of the CDC25A protein, and its impact on prognosis of NSCLC patients.Here we report a novel CDC25A transcript variant with codon 110 (Glutamine) deletion, that we termed CDC25A(Q110del) in NSCLC cells. In 9 (75%) of the 12 NSCLC cell lines, CDC25A(Q110del) expression accounted for more than 20% of the CDC25A transcripts. Biological effects of CDC25A(Q110del) were investigated in H1299 and HEK-293F cells using UV radiation, flowcytometry, cyclohexamide treatment, and confocal microscopy. Compared to CDC25A(wt), CDC25A(Q110del) protein had longer half-life; cells expressing CDC25A(Q110del) were more resistant to UV irradiation and showed more mitotic activity. Taqman-PCR was used to quantify CDC25A(Q110del) expression levels in 88 primary NSCLC tumor/normal tissue pairs. In patients with NSCLC, Kaplan Meier curves showed tumors expressing higher levels of CDC25A(Q110del) relative to the adjacent lung tissues to have significantly inferior overall survival (P = .0018).Here we identified CDC25A(Q110del) as a novel transcriptional variant of CDC25A in NSCLC. The sequence-specific nature of the abnormality could be a prognostic indicator in NSCLC patients as well as a candidate target for future therapeutic strategies.