Rs-10889677 variant in interleukin-23 receptor may contribute to creating an inflammatory milieu more susceptible to bladder tumourigenesis: report and meta-analysis.

Bladder cancer (BLC) is a recurrent high-risk malignancy typified by an inherent localised chronic inflammation. IL-23-receptor (IL-23R), as a positive regulator in the priming of T helper-17 cells, is regarded a principal coordinator of inflammation-propelled neoplasia. In this article, we indented firstly to scrutinise the influence of rs10889677"A/C" SNP located in IL-23R-gene on BLC development and progression among Egyptians. Findings revealed that the rs10889677"C" allele was significantly associated with the increased BLC risk and its higher frequencies were plainly noticeable in high-grade and invasive tumours when applied the dominant/homozygous/allelic genetic models. Under the same genetic models, elevated serum levels of IL-23R protein in BLC patients were pertinently correlated with the rs10889677"A/C" polymorphism. As a corollary, the frequent up-regulation of IL-23R exerts a subsequent activation of the IL-23/17 inflammatory axis. That is experienced as a drastic increase in IL-23 and IL17 levels under the dominant/homozygous/heterozygous/recessive models. Second, study further described how the rs10889677 variant confers its pro-tumoural influences on IL-23R-bearing immune cells, involving tumour-associated macrophages (TAMs), natural killers (NKs) and CD4+ T-helper cells. When the dominant model was adopted, it was observed that patients bearing the rs10889677 "C" allele had lower counts of IL-23R-positive CD56+NKs and CD4+ T-cells, in tandem with higher levels of IL-23R-positive CD14+ TAMs compared with those with rs10889677 "A" allele. To entrench the idea, we did a meta-analysis on BLC patients from three different ethnicities (Asian, Caucasians and African). We observed that rs10889677"SNP" is significantly correlated with increased risk of BLCs in the overall population using over-dominant model. Consequently, authors suggested that the rs10889677 variant could be directly implicated in developing inflammatory environment more prone to generating malignancy.

Rs-1884444 G/T variant in IL-23 receptor is likely to modify risk of bladder urothelial carcinoma by regulating IL-23/IL-17 inflammatory pathway.

Bladder urothelial carcinoma (BUC) is a chronic relapsing urological malignancy, which poses a serious threat to human life. Non-resolving chronic-inflammation at the neoplastic site is associated consistently with inducing tumor-progression and poor patient outcomes. Interleukin 23 receptor (IL-23R) is a key element in T-helper 17 cell-mediated inflammatory process, that plays a critical role in orchestrating tumor-promoting inflammation. Therefore, we hypothesized that potentially functional genetic variant rs1884444 G/T of IL-23R may modify BUC risk. To validate this hypothesis, our findings demonstrated that the rs1884444 G/T variant was significantly associated with a reduced risk of BUC compared to controls observed under allelic (T vs. G) and dominant (GT + TT vs. GG) models (P < 0.05). In addition, the frequency of the T-allele has dropped to very low values in the case of high-grades and invasive-tumors (P < 0.05). Thus, T-allele has emerged as a reliable genetic marker for good prognosis of BUC. In tumorgenesis, the binding-affinity of the receptor seemed to be distorted by the effect of the non-conservative G/T variation, which in turn caused the IL-23/IL-17 pathway to be disabled. This was recognized by low levels of IL-23 and IL-17 in the serum of patients, under the influence of all the tested genetic models (P < 0.01). Results also indicated that the level of the receptor-bearing immune cells could be altered in response to the G/T protective effect. For example, the median counts of T-helper CD4+ cells and CD56+ natural killers increased significantly in conjunction with the decrease in the median count of CD14+ tumor-associated-macrophages under the dominant model. Nevertheless, the causative link between this subtle polymorphism and the immune-surveillance against BUC needs further in-depth investigation. Overall, we concluded that the rs-1884444 G/T variant is highly-associated with a reduction in the BUC risk, which may occur via deregulation of the IL-23/IL-17 pathway.