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Background The incidence of bladder urothelial carcinoma (UC), a common malignancy of the urinary tract, is approximately three times higher in men than in women. High expression of the mitotic kinase BUB1 is associated with the occurrence and development of several cancers, although the relationship between BUB1 and bladder tumorigenesis remains unclear. Methods Using a microarray approach, we found increased BUB1 expression in human BCa. The association between BUB1 and STAT3 phosphorylation was determined through molecular and cell biological methods. We evaluated the impact of pharmacologic inhibition of BUB1 kinase activity on proliferation and BCa progression in vitro and in vivo. Results In this study, we found that BUB1 expression was increased in human bladder cancer (BCa). We further identified through a series of molecular and cell biological approaches that BUB1 interacted directly with STAT3 and mediated the phosphorylation of STAT3 at Ser727. In addition, the findings that pharmacologic inhibition of BUB1 kinase activity significantly suppressed BCa cell proliferation and the progression of bladder cancer in vitro and in vivo were further verified. Finally, we found that the BUB1/STAT3 complex promoted the transcription of STAT3 target genes and that depletion of BUB1 and mutation of the BUB1 kinase domain abrogated this transcriptional activity, further highlighting the critical role of kinase activity in the activation of STAT3 target genes. A pharmacological inhibitor of BUB1 (2OH-BNPP1) was able to significantly inhibit the growth of BCa cell xenografts. Conclusion This study showed that the BUB1 kinase drives the progression and proliferation of BCa by regulating the transcriptional activation of STAT3 signaling and may be an attractive candidate for therapeutic targeting in BCa.

Death receptor 4 (DR4) is an important mediator of apoptosis, and its dysfunction may be related to carcinogenesis and cancer development. We hypothesized that common variants in the DR4 gene are associated with risk of bladder cancer and test this hypothesis in a case-control study of 368 bladder cancer patients and 368 cancer-free controls. We genotyped six tagging single nucleotide polymorphisms (tagSNPs) in these subjects and found a significantly increased risk of bladder cancer associated with the SNP1-397GT/TT genotype (adjusted OR=1.55; 95% CI=1.15-2.09) compared with the GG genotype. This increased risk was more pronounced for superficial bladder cancer. A luciferase assay, performed in vitro, revealed that the -397T allele had a lower transcriptional activity than the -397G allele. Multifactor dimensionality reduction (MDR) analysis indicated that the two-factor model including -397G>T and pack-years of smoking was best for predicting bladder cancer risk. Moreover, a significant additive (but not multiplicative) interaction, was found between the -397G>T polymorphism and smoking on bladder cancer risk. In conclusion, genetic variants of the DR4 gene may be involved in the etiology of bladder cancer, and our findings need further validation by larger studies.

Inflammatory factors may promote carcinogenesis. Macrophage migration inhibitory factor (MIF), which is derived from T-cell, known as a member of the transforming growth factor-β (TGF-β) superfamily, plays an important role in the pro- and anti-inflammatory response to infection and in the etiology of bladder cancer. We hypothesized that MIF-173 locus polymorphism might contribute to genetic susceptibility to bladder cancer. In a hospital-based case–control study of 325 patients with bladder cancer and 345 cancer-free controls frequency-matched by age, sex, smoking status, and alcohol use, we genotyped the MIF polymorphism and analyzed immunohistochemical stained operational bladder cancer tissue sections for MIF. We found that individuals with GC/CC genotype had a significantly decreased risk of bladder cancer (adjusted OR = 0.57, 95% CI, 0.41–0.79) than those with GG genotype. In the stratification analysis, we found that the decreased risk was more pronounced among older subjects (adjusted OR = 0.56, 95% CI, 0.39–0.81), men (0.47, 0.33–0.68), smokers (0.54, 0.35–0.85), and ever-drinkers (0.44, 0.27–0.71). The percentage of positive staining in the cytoplasm and nucleus in the normal and bladder cancer with CC/GC genotype tissues was higher than that of GG genotype bladder cancer tissue(39.1% vs. 75.0% in strong staining for GG and GC/CC genotypes, respectively, P = 0.028). In conclusion, MIF -173G>C polymorphism may play a role in the etiology of bladder cancer in southern Chinese population. Large studies are warranted to validate our findings.

Folate deficiency due to the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) variants leads to carcinogenesis by affecting DNA synthesis, repair, and methylation. We hypothesized that the MTHFR C677T, A1298C, and MS A2756G polymorphisms are associated with risk of bladder cancer. In a case–control study of 239 bladder cancer cases and 250 cancer-free controls, we found that the MTHFR 677TT genotype was statistically significantly associated with an increased risk of bladder cancer compared with the 677CC genotype (OR = 2.06, 95% CI = 1.16–3.64). Furthermore, the TA haplotype was associated with a significantly increased bladder cancer risk (OR = 1.38, 95% CI = 1.05–1.81) than was the most common haplotype, CA (e.g., CA denotes MTHFR 677C -1298A). We also found that the combined genotypes with 4–6 variant (risk) alleles (i.e., MTHFR 677T, 1298A, and MS 2756G alleles) were associated with an increased risk of bladder cancer (OR = 1.62, 95% CI = 1.03–2.53) compared with those with 0–3 variants, and this increased risk was more pronounced among subgroup of older people (OR = 1.71, 95% CI = 1.03–2.83). A meta-analysis of seven studies did not show a significant risk of bladder cancer in the MTHFR polymorphisms. The MTHFR polymorphisms and their haplotypes appear to jointly contribute to risk of bladder cancer.