ABSTRACT
BACKGROUND: BORIS/CTCFL, a paralog of CTCF and member of the cancer-testicular antigen family, is abnormally activated in multiple cancers. OBJECTIVE: We investigated the relationship between polymorphic variants of the BORIS minisatellite 2 (BORIS-MS2), located within the 5' upstream promoter region of BORIS, and bladder cancer. METHODS: We used case-control study with 516 controls and 113 bladder cancer patients. To evaluate whether minisatellite variants play a role in BORIS expression, we examined the transcript levels of a reporter gene linked to these minisatellites in cell lines. We also examined BORIS expression in cancerous and non-cancerous bladder tissue. RESULTS: A statistically significant association was identified between the short rare allele (13-repeat) and bladder cancer incidence (odds ratio (OR) 2.97, 95% confidence interval (CI) [1.14, 7.74]; P = 0.020). In particular, short rare alleles in the younger group (aged < 65) were associated with statistically significant increase in bladder cancer risk (OR 5.38, CI [1.32, 21.87]; P = 0.01). The BORIS-MS2 region acted as a negative regulator, and the expression level of the luciferase reporter in bladder cancer cells was less effectively inhibited than in normal cells. Furthermore, the expression of BORIS mRNA significantly differed (P < 0.05) between normal and cancerous muscle-invasive bladder cancer tissues, and relationship to clinical parameters was observed. CONCLUSIONS: The short rare allele of BORIS-MS2 could be used to identify bladder cancer risk. BORIS expression levels have been shown to increase with the progression of bladder cancer, could be used as a biomarker for its progression.
Subject(s)
Biomarkers, Tumor/genetics , DNA-Binding Proteins/genetics , Polymorphism, Genetic , Urinary Bladder Neoplasms/genetics , Adult , Aged , Biomarkers, Tumor/metabolism , Cell Line, Tumor , DNA-Binding Proteins/metabolism , Female , HEK293 Cells , Humans , Male , Middle Aged , Minisatellite Repeats , Promoter Regions, Genetic , Urinary Bladder Neoplasms/pathologyABSTRACT
Recurrence is a serious problem in patients with bladder cancer. The hypothesis for recurrence was that the proliferation of drug-resistant cells was reported, and this study focused on drug resistance due to drug efflux. Previous studies have identified FOXM1 as the key gene for recurrence. We found that FOXM1 inhibition decreased drug efflux activity and increased sensitivity to Doxorubicin. Therefore, we examined whether the expression of ABC transporter gene related to drug efflux is regulated by FOXM1. As a result, ABCG2, one of the genes involved in drug efflux, has been identified as a new target for FOXM1. We also demonstrated direct transcriptional regulation of ABCG2 by FOXM1 using ChIP assay. Consequently, in the presence of the drug, FOXM1 is proposed to directly activate ABCG2 to increase the drug efflux activation and drug resistance, thereby involving chemoresistance of bladder cancer cells. Therefore, we suggest that FOXM1 and ABCG2 may be useful targets and important parameters in the treatment of bladder cancer. [BMB Reports 2018; 51(2): 98-103].
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Drug Resistance, Neoplasm , Forkhead Box Protein M1/metabolism , Neoplasm Proteins/metabolism , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , Doxorubicin , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Forkhead Box Protein M1/genetics , Gene Expression Regulation, Neoplastic , Humans , Neoplasm Proteins/genetics , Promoter Regions, Genetic/genetics , Protein Binding/geneticsABSTRACT
The dopamine transporter SLC6A3 (DAT1) mediates uptake of dopamine into presynaptic terminals. In addition, in previous reports, hypertensive rats were associated with DAT gene, but the genetic association with SLC6A3 and hypertension is still unknown. We examined the distribution of variable number of tandem repeats (VNTRs) and conducted polymorphic analysis of the entire region of SLC6A3. Ten VNTR regions (MS1-10) were revealed throughout the intronic and UTRs; seven VNTR regions were newly isolated and three VNTRs were previously reported. Four VNTR regions (SLC6A3-MS1, -MS4, -MS8 [rs3836790], and -MS9 [rs28363170]) showed polymorphism and these loci were found to be transmitted through meiosis following Mendelian inheritance. These VNTR polymorphisms may be useful markers for paternity mapping and DNA fingerprinting. Furthermore, we also conducted a case-control study between the controls and essential hypertensive cases. Analysis of the genotypes of SLC6A3-MS8 (rs3836790) revealed that having an 8/6-repeat allele, which was only detected in hypertensive cases, was associated with hypertension (p < 0.05). Additional significant association was identified between the short 7-repeat allele of SLC6A3-MS9 (rs28363170) and the occurrence of hypertension (odds ratio 2.02; p < 0.05). These results revealed the genetic association between SLC6A3 and hypertension, and the specific VNTR alleles of SLC6A3 may be a risk factor for hypertension.
