MDR1 Gene Overexpression and Altered Degree of Methylation at the Promoter Region in Bladder Cancer during Chemotherapeutic Treatment

• Published in: Clinical cancer research 2000-12, Vol.6 (12), p.4618-4627
• Main Authors: Tada, Y, Wada, M, Kuroiwa, K, Kinugawa, N, Harada, T, Nagayama, J, Nakagawa, M, Naito, S, Kuwano, M
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - therapeutic use; ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis; Blotting, Southern; CpG Islands; DNA Methylation; Female; Gene Expression Regulation, Neoplastic; Genes, MDR - genetics; Humans; Immunohistochemistry; Male; Middle Aged; Phenotype; Polymerase Chain Reaction; Prognosis; Promoter Regions, Genetic; Recurrence; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleases - metabolism; RNA, Messenger - metabolism; Treatment Outcome; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology
• ISSN: 1078-0432; 1557-3265

Overexpression of the multidrug resistance 1 ( MDR1 ) gene is closely associated with the clinical outcome of hematopoietic malignancies, but the alteration of its expression during chemotherapeutic treatment and the precise mechanism underlying MDR1 gene overexpression in solid tumors remains unclear. We determined the expression and degree of methylation at the promoter of the MDR1 gene in bladder cancer. The mRNA levels of the MDR1 gene were found to be markedly enhanced, 3.5- to 5.7-fold higher in bladder cancers after chemotherapeutic treatment than those in untreated primary tumors. The MDR1 gene was overexpressed in recurrent tumors in 89% of patients who showed re-recurrence, whereas overexpression was observed in 25% of the patients without re-recurrence. A statistically significant inverse correlation existed between MDR1 expression and the methylation of 5′CpG sites at the promoter in patients with bladder cancer after chemotherapeutic treatment, with the degree of methylation at several CpG sites, rather than other specific sites, involved in this regulation. Consistent with the increase in MDR1 expression, the frequency of patients with a hypermethylated promoter decreased to 50 and 17% after intravesical and systemic chemotherapy, respectively. Thus, overexpression of the MDR1 gene might be a prognostic marker for intravesical recurrence, whereas methylation of the promoter region negatively regulates MDR1 expression and the appearance of multidrug resistance mediated by P-glycoprotein in bladder cancers.