Human DNA polymerase iota (pol ι) possesses high error-prone DNA replication features and performs translesion DNA synthesis. It may be specialized and strictly regulated in normal mammalian cells. Dysregulation of pol ι may contribute to the acquisition of a mutator phenotype. However, there are few reports describing the transcription regulatory mechanism of pol ι, and there is controversy regarding its role in carcinogenesis. In this study, we performed the deletion and point-mutation experiment, EMSA, ChIP, RNA interference and western blot assay to prove that c-Jun activated by c-Jun N-terminal kinase (JNK) regulates the transcription of pol ι in normal and cancer cells. Xeroderma pigmentosum group C protein (XPC) and ataxia-telangiectasia mutated related protein (ATR) promote early JNK activation in response to DNA damage and consequently enhance the expression of pol ι, indicating that the novel role of JNK signal pathway is involved in DNA damage response. Furthermore, associated with elevated c-Jun activity, the overexpression of pol ι is positively correlated with the clinical tumor grade in 97 bladder cancer samples and may contribute to the hypermutagenesis. The overexpressed pol ι-involved mutagenesis is dependent on JNK/c-Jun pathway in bladder cancer cells identifying by the special mutation spectra. Our results support the conclusion that dysregulation of pol ι by JNK/c-Jun is involved in carcinogenesis and offer a novel understanding of the role of pol ι or c-Jun in mutagenesis.

Notch3 overexpression enhances progression and chemoresistance of urothelial carcinoma

Background: A routine blood examination is one of the most rapid, convenient and inexpensive clinical examinations that can reflect a patient’s inflammatory status and other blood conditions, and the prognostic value of routine preoperative blood parameters in MIBC patients is still unclear, so we evaluated the prognostic value of routine preoperative blood parameters in muscle-invasive bladder cancer (MIBC) following radical cystectomy (RC). Methods: Data on 202 patients with MIBC who underwent RC at our institution were retrospectively collected between October 2007 and August 2018. The median preoperative neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and hemoglobin (HGB) values were used as cutoffs to form the low and high NLR, low and high PLR, and low and high HGB groups, respectively. The clinicopathologic characteristics of each group were compared by chi-square and t tests. Kaplan-Meier survival and multivariate Cox regression analyses were used to analyze prognosis. Results: The median NLR, PLR and HGB values were 2.42, 112 and 125 g/L, respectively. Kaplan-Meier results showed that the low HGB group had poor progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). A high NLR and high PLR groups correlated only with poor OS. Multivariate Cox analyses showed that pathological T3/4 stage, positive lymph node status and low HGB were independent risk factors for PFS, CSS and OS, and age was the only independent risk factor for OS. Conclusion: Preoperative peripheral blood HGB is an independent risk factor for the prognosis of MIBC patients. These data suggest that HGB may be a useful prognostic marker for MIBC patients undergoing RC.

Human renal cancer is extremely resistant to chemotherapy and radiation therapy. This clinical characteristic reduces the efficacy of chemotherapeutic agents in the treatment of recurrence or metastasis following surgical resection. Understanding the mechanism of chemotherapy resistance in renal cell carcinoma remains a significant challenge. In this study, we have shown that varied level of XPF expression was organ‐tissue specific by comparing human renal cancer, bladder cancer, testicular cancer and their normal tissue counterparts, respectively. The expression of XPF was significantly higher in renal cancer than in bladder cancer and testicular cancer and correlated with the clinical characteristic of their chemotherapeutics sensitivity. These novel findings proposed that the intrinsic chemoresistance of human renal cell carcinomas might be derived from the high level of XPF expression. In a panel of five cancer cell lines, decreasing cisplatin sensitivity correlated with increasing levels of XPF expression. Knockdown of XPF expression not only increased sensitivity of renal carcinoma cells to cisplatin treatment by affecting the DNA damage response, including DNA repair, cell cycle regulation and apoptosis, but also increased senescence of renal cancer cell. Furthermore, experiment in vivo confirmed that silenced XPF significantly increased the sensitivity and survival following treatment with cisplatin in xenograft mice bearing renal cell tumor. These findings firstly uncover a partial mechanism of intrinsic chemoresistance in renal cancer and may provide a new approach to break through the obstacle of intrinsic chemoresistance by targeting the XPF protein with a potential new inhibitor.

Inherited polymorphisms in the XPC gene that lead to a reduction in DNA repair capacity may increase susceptibility to bladder cancer. We investigated three polymorphisms of the XPC gene (PAT, Ala499Val and Lys939Gln) in 600 subjects with bladder cancer and in 609 healthy controls by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a Chinese Han population. Smoking was associated with a significant increase in the risk for bladder cancer (OR, 2.48; 95% CI, 1.91-3.21). The risk was greater among heavy smokers (OR, 3.09, 95% CI, 2.24-4.25) compared to light smokers (OR, 1.91, 95% CI, 1.37-2.68). In three polymorphisms of XPC, only the XPC-PAT variant genotype exhibited a significantly increased risk for bladder cancer. When the total smoking exposure-gene interaction was examined, the three polymorphisms did not exhibit any significant effect in never smokers but a significant dose-response association in light or heavy smokers. Especially, the bladder cancer risk was significantly elevated among the polymorphisms of XPC-PAT(+/-) (OR, 2.56, 95% CI, 1.56-4.21, p<0.001; OR, 3.41, 95% CI, 2.19-5.29, p<0.001) and XPC-PAT(+/+) (OR, 3. 00, 95% CI, 1.31-6.88, p=0.009; OR, 6. 78, 95% CI, 3.00-15.54, p<0.001) with either light or heavy smoking exposure, respectively. XPC-PAT polymorphisms contribute to the risk for developing bladder cancer and an elevated risk of bladder cancer was significantly associated with the gene-environment (smoking) interaction in a Chinese Han population.

Here, we attempt to better define the long-term outcomes of radical cystectomy (RC) for urothelial carcinoma (UC) in a Chinese population and to investigate the relationship between EZH2 protein expression levels and the clinicopathological parameters and outcomes in patients with UC. We detected the relative EZH2 protein expression levels by immunohistochemistry in tumour specimens from a cohort of 189 Chinese UC patients. In patients who underwent RC, the 5-year cancer-specific survival (CSS) and overall survival (OS) were 69% and 61% respectively. EZH2 expression was increased in UC compared with normal urothelium. The expression levels of EZH2 were elevated in parallel with tumour stage (p = 0.001) and tumour grade (p = 0.001) and were increased in cases with lymph node metastasis compared with node-negative cases (p = 0.018). Kaplan-Meier analyses showed that higher EZH2 expression was related to significantly shorter CSS and OS in patients who underwent RC. High EZH2 expression was associated with worse CSS (HR = 3.51; p = 0.037) and OS (HR = 2.15; p = 0.047) in the univariate analysis, but only lymph node invasion maintained its predictive value for CSS in a multivariate model. This contemporary and homogeneous single-centre series found acceptable outcomes for Chinese UC patients who underwent RC. Clinically, our retrospective studies suggest that EZH2 levels can be used to identify more aggressive phenotypes in UC patients, thereby improving our prognostic knowledge.