Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan, ROC; Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan, ROC.
Urol Oncol. 2020 May;38(5):465-475. doi: 10.1016/j.urolonc.2020.02.017. Epub 2020 Mar 18.
Urothelial carcinomas (UCs) are highly prevalent in patients with end-stage renal disease. Chronic kidney disease (CKD) is the predecessor of end-stage renal disease, and it is also associated with UC. However, the interplay between CKD and UC lacks solid evidence. Acrolein is produced by polyamines and has been suggested to be the uremic "toxin." The level of acrolein correlates well with chronic renal failure. We recently found that acrolein-induced DNA damage and inhibited DNA repair in urothelial cells, which contribute to bladder cancer. Therefore, we hypothesize that acrolein is involved in the formation of UC in patients with CKD.
A total of 62 UC patients and 43 healthy control subjects were recruited. Acrolein-DNA (Acr-dG) adducts and p53 gene mutations in UC tissues, plasma acrolein-protein conjugates (Acr-PC) and S-(3-hydroxypropyl)-N-acetylcysteine levels, and urinary Acr metabolites were analyzed in these patients.
Acr-dG levels were statistically correlated with CKD stages in UC patients (P < 0.01). Most p53 mutations were G to A and G to T mutations in these patients, and 50% of mutations at G:C pairs occurred in CpG sites, which is similar to the mutational spectra induced by Acr-dG adducts. Acr-PC levels in the plasma of UC patients with CKD were significantly higher than those of control subjects (P < 0.001). Altered urinary S-(3-hydroxypropyl)-N-acetylcysteine was also found in UC patients with CKD compared to control subjects (P < 0.005).
These results indicate that acrolein acts as an endogenous uremic toxin and contributes to UC formation in patients with CKD.
在终末期肾病患者中，尿路上皮癌（UC）非常普遍。慢性肾脏病（CKD）是终末期肾病的前身，也与 UC 有关。然而，CKD 和 UC 之间的相互作用缺乏确凿的证据。丙烯醛是由多胺产生的，被认为是尿毒症的“毒素”。丙烯醛的水平与慢性肾功能衰竭密切相关。我们最近发现，丙烯醛诱导的尿路上皮细胞 DNA 损伤和抑制 DNA 修复，这有助于膀胱癌的发生。因此，我们假设丙烯醛参与了 CKD 患者 UC 的形成。
共招募了 62 例 UC 患者和 43 例健康对照者。分析 UC 组织中的丙烯醛-DNA（Acr-dG）加合物和 p53 基因突变、血浆丙烯醛-蛋白质共轭物（Acr-PC）和 S-（3-羟基丙基）-N-乙酰半胱氨酸水平以及尿中 Acr 代谢物。
Acr-dG 水平与 UC 患者的 CKD 分期呈统计学相关（P < 0.01）。这些患者的大多数 p53 突变是 G 到 A 和 G 到 T 的突变，50%的突变发生在 CpG 位点的 G:C 对，这与 Acr-dG 加合物诱导的突变谱相似。CKD 合并 UC 的患者血浆中 Acr-PC 水平明显高于对照组（P < 0.001）。与对照组相比，CKD 合并 UC 的患者尿中 S-（3-羟基丙基）-N-乙酰半胱氨酸也发生了改变（P < 0.005）。
这些结果表明，丙烯醛作为一种内源性尿毒症毒素，促进 CKD 患者 UC 的形成。
