Gene Expression and DNA Methylation Status of Glutathione S-Transferase Mu1 and Mu5 in Urothelial Carcinoma

Abstract

Bladder cancer is highly recurrent after therapy, which has an enormous impact on the health and financial condition of the patient. It is worth developing diagnostic tools for bladder cancer. In our previous study, we found that the bladder carcinogen BBN increased urothelial global DNA CpG methylation and decreased GSTM1 protein expression in mice. Here, the correlation of BBN-decreased GSTM1 and GSTM gene CpG methylation status was analyzed in mice bladders. BBN treatment decreased the protein and mRNA expression of GSTM1, and the CpG methylation ratio of GSTM1 gene promoter was slightly increased in mice bladders. Unlike mouse GSTM1, the human GSTM1 gene tends to be deleted in bladder cancers. Among 7 human bladder cancer cell lines, GSTM1 gene is really null in 6 cell lines except one, T24 cells. The CpG methylation level of GSTM1 was 9.9% and 5-aza-dC did not significantly increase GSTM1 protein and mRNA expression in T24 cells; however, the GSTM5 gene was CpG hypermethylated (65.4%) and 5-aza-dC also did not affect the methylation ratio and mRNA expression. However, in other cell lines without GSTM1, 5-aza-dC increased GSTM5 expression and decreased its CpG DNA methylation ratio from 84.6% to 61.5% in 5637, and from 97.4% to 75% in J82 cells. In summary, two biomarkers of bladder tumor were provided. One is the GSTM1 gene which is down-regulated in mice bladder carcinogenesis and is usually deleted in human urothelial carcinoma, while the other is the GSTM5 gene, which is inactivated by DNA CpG methylation.

The interaction of arsenic and N-butyl-N-(4-hydroxybutyl)nitrosamine on urothelial carcinogenesis in mice

“…It is known that BBN changes the protein expression of GSTM1, GSTO1 and NQO1 in the mouse urothelium after a 20-week treatment [ 22 , 35 ]. In this study, BBN also changed their expression, but arsenic did not alter this effect.…”

“…In this study, BBN also changed their expression, but arsenic did not alter this effect. GSTM1, an antioxidant enzyme related to bladder cancer development [ 36 ], is down-regulated in protein and mRNA levels by BBN that are partially mediated by DNA methylation [ 35 ]. The decrease in GSTM1 may be involved in BBN-induced bladder carcinogenesis, but not directly related to arsenic.…”

“…The tumor suppressor gene p21 protein expression was decreased by either BBN or arsenic alone ( Fig 3E ). It is known that the decreased p21 expression by BBN is not mediated by transcription inhibition in mouse bladders [ 35 ]. However, in mouse JB6 epidermal skin cells, arsenic decreases p21 expression through the inhibition of p53 phosphorylation and transactivation [ 37 ].…”

Effect of Smoke Exposure on Chronic Inflammation and P53 Expression in Bladder Epithelial

“…44 Previous study confirmed three primary genetic alterations which were consistently affect pathogenesis of papillary precursor lesion and non-muscle invasive bladder cancer (NMI-BC) including tyrosine kinase receptor fibroblast growth factor receptor 3 (FGFR-3), phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA) and Harvey rat sarcoma viral oncogene homolog (H-RAS). 45,46 In the other hand, alteration in tumor suppressor genes such as p16, Rb99 TP53 was oncogenesis machinery for the development of precursor neoplastic of muscle invasive bladder cancer (MI-BC) termed as CIS and urothelial dysplasia. Evidence also showed that the progression from papillary NMI-BC into high grade MI-BC was depend on TP53 and Rb activation.…”

MicroRNAs in Smoking-Related Carcinogenesis: Biomarkers, Functions, and Therapy

“…Some mechanisms of carcinogenesis in the urinary tract have been suggested. For example, DNA methylation retains cell proliferation in the normal urothelium [ 63 , 64 , 65 , 66 ]. One group of gene clusters was estimated taking into account the important role of miRNAs.…”