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.

中文翻译：

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IL-23 受体中的 Rs-1884444 G/T 变体可能通过调节 IL-23/IL-17 炎症通路来改变膀胱尿路上皮癌的风险

膀胱尿路上皮癌（BUC）是一种慢性复发性泌尿系统恶性肿瘤，对人类生命构成严重威胁。肿瘤部位的非解决性慢性炎症始终与诱导肿瘤进展和患者预后不良有关。白细胞介素 23 受体 (IL-23R) 是 T 辅助细胞 17 细胞介导的炎症过程中的关键元素，在协调肿瘤促进炎症中起关键作用。因此，我们假设 IL-23R 的潜在功能性遗传变异 rs1884444 G/T 可能会改变 BUC 风险。为了验证这一假设，我们的研究结果表明，与在等位基因（T 与 G）和显性（GT + TT 与 GG）模型下观察到的对照相比，rs1884444 G/T 变体与 BUC 风险降低显着相关（P < 0.05)。此外，在高级别和侵袭性肿瘤的情况下，T 等位基因的频率已降至非常低的值（P < 0.05）。因此，T等位基因已成为BUC预后良好的可靠遗传标志物。在肿瘤发生中，受体的结合亲和力似乎受到非保守 G/T 变异的影响，进而导致 IL-23/IL-17 通路失效。在所有测试的遗传模型的影响下，患者血清中的低水平 IL-23 和 IL-17 都认识到了这一点（P < 0.01）。结果还表明，携带受体的免疫细胞的水平可以响应 G/T 保护作用而改变。例如，在优势模型下，辅助 T 细胞 CD4+ 细胞和 CD56+ 自然杀伤细胞的中位数计数显着增加，同时 CD14+ 肿瘤相关巨噬细胞的中位数计数减少。然而，这种微妙的多态性与针对 BUC 的免疫监视之间的因果关系需要进一步深入研究。总体而言，我们得出结论，rs-1884444 G/T 变体与 BUC 风险的降低高度相关，这可能通过 IL-23/IL-17 通路的失调而发生。