Topoisomerase IIα gene expression is regulated by the p53 tumor suppressor gene in nonsmall cell lung carcinoma patients

Abstract

BACKGROUND Topoisomerase IIα (Topo IIα) is an essential nuclear enzyme for chromosome segregation during mitosis. Previous experimental studies using cell lines reported that Topo IIα expression was negatively regulated by wild‐type p53 through the gene's promoter region. METHODS Surgically resected tumor specimens from 98 nonsmall cell lung carcinoma (NSCLC) patients who were not treated with preoperative chemotherapy were studied. Quantitative reverse‐transcription polymerase chain reaction analysis was done to evaluate Topo IIα gene expression. Polymerase chain reaction single strand conformation polymorphism following sequencing was performed to investigate mutations of p53. RESULTS Topo IIα gene expression in squamous cell carcinomas was significantly higher than in adenocarcinomas (P = 0.0007). Topo IIα gene expression in moderately differentiated tumors and poorly differentiated tumors was significantly higher than in well differentiated tumors (P = 0.0032 and P = 0.0005, respectively). Thirty nine tumors (40%) had mutations of p53. Topo IIα gene expression in tumors with mutant p53 was significantly higher than in those with wild‐type p53 (P = 0.0224). CONCLUSIONS The current study suggests that Topo IIα gene expression is regulated by p53 gene status in NSCLC patients and that the overexpression of Topo IIα induced by mutant p53 might cause more aggressive carcinogenesis. Cancer 2002;94:2239–47. © 2002 American Cancer Society. DOI 10.1002/cncr.10450

Mining expression and prognosis of topoisomerase isoforms in non-small-cell lung cancer by using Oncomine and Kaplan–Meier plotter

“…The high expression of TOP2A in tumor tissue predicted poor prognosis in some tumor patients [28, 54–56] and also promoted lymph node metastasis and distant metastasis in malignant tumors [29, 57]. There was not a statistically significant association of TOP2A expression with clinical parameters, such as age, gender or pathological tumor stage [30, 31]. In our study, over-expression of TOP2A was associated with significantly worse OS in all NSCLC patients as well as Ade patients, but not significantly worse OS in SCC patients.…”

HMGB1 and HMGB2 proteins up-regulate cellular expression of human topoisomerase II

“…HMGB1 and HMGB2 proteins have previously been reported to promote binding of p53 (or its close relative, p73) to their specific DNA-binding sites by bending and specific p53–HMGB1/2 interactions (20,59). Whether the latter interactions could counteract or even enhance the reported p53-mediated inhibition of the topo IIα gene promoter activity (20,24,45,60) is unclear. Interestingly, the catalytic activity of topo IIα was stimulated by p53 (46), albeit by a mechanism different from that reported by HMGB1 (11).…”

Synergistic effects of the purine analog sulfinosine and curcumin on the multidrug resistant human non-small cell lung carcinoma cell line (NCI-H460/R)

“…45,46 Clinical studies revealed a correlation between mutational status of p53 and topo IIα expression and confirmed the regulation of topo IIα transcription by p53 in NSCLC patients. 37,47 We hypothesize that the decrease in topo IIα gene expression, a mechanism of acquired resistance, was neutralized by its release from transcriptional suppression as a result of mutations in p53.…”