Differentiation-associated urothelial cytochrome P450 oxidoreductase predicates the xenobiotic-metabolizing activity of "luminal" muscle-invasive bladder cancers.
Differentiation-associated urothelial cytochrome P450 oxidoreductase predicates the xenobiotic-metabolizing activity of "luminal" muscle-invasive bladder cancers.
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DOI：
10.1002/mc.22784
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发表时间：
2018-05
影响因子：
4.6
通讯作者：
Southgate J
中科院分区：
文献类型：
--
作者：
Baker SC;Arlt VM;Indra R;Joel M;Stiborová M;Eardley I;Ahmad N;Otto W;Burger M;Rubenwolf P;Phillips DH;Southgate J
上皮组织对外源性物质的肝外代谢已演变为一种自我防御机制，但有可能导致致癌物的局部活化。膀胱上皮（尿路上皮）浸泡在排泄的尿液毒物和致癌物中。这项研究揭示了分化如何影响细胞色素P450（NADPH）活性和NADPH：P450氧化还原酶（POR）的作用。CYP 1A 1和CYP 1B 1转录物在体外维持在未分化和功能性屏障形成分化状态的正常人尿路上皮（NHU）细胞中可诱导。然而，在分化的NHU细胞培养物中主要检测到乙氧基试卤灵O-脱乙基化（EROD）活性、反应性BaP代谢物和BaP-DNA加合物的产生。这种功能的获得归因于POR的表达，POR是所有CYP的必需电子供体，其作为尿路上皮分化的一部分显著上调。肌层浸润性膀胱癌（MIBC）的免疫组织学显示POR表达的显著总体抑制。基于GATA 3和细胞角蛋白5/6标记，将MIBC活检分为“管腔”和“基底”组，显示分化管腔肿瘤亚组的POR过表达。在膀胱癌细胞系中，CYP 1活性在基础PORlo T24和SCaBER细胞中不可检测/低，并且在管腔POR过表达RT 4和RT 112细胞中高于分化的NHU细胞，表明CYP 1功能与膀胱癌的分化状态相关。本研究将POR确立为代谢潜力的预测性生物标志物。这在膀胱癌发生中对致癌物的肝脏与局部活化有影响，并作为MIBC对前药治疗反应的潜在功能预测因子。
Extra‐hepatic metabolism of xenobiotics by epithelial tissues has evolved as a self‐defence mechanism but has potential to contribute to the local activation of carcinogens. Bladder epithelium (urothelium) is bathed in excreted urinary toxicants and pro‐carcinogens. This study reveals how differentiation affects cytochrome P450 (CYP) activity and the role of NADPH:P450 oxidoreductase (POR). CYP1A1 and CYP1B1 transcripts were inducible in normal human urothelial (NHU) cells maintained in both undifferentiated and functional barrier‐forming differentiated states in vitro. However, ethoxyresorufin O‐deethylation (EROD) activity, the generation of reactive BaP metabolites and BaP‐DNA adducts, were predominantly detected in differentiated NHU cell cultures. This gain‐of‐function was attributable to the expression of POR, an essential electron donor for all CYPs, which was significantly upregulated as part of urothelial differentiation. Immunohistology of muscle‐invasive bladder cancer (MIBC) revealed significant overall suppression of POR expression. Stratification of MIBC biopsies into “luminal” and “basal” groups, based on GATA3 and cytokeratin 5/6 labeling, showed POR over‐expression by a subgroup of the differentiated luminal tumors. In bladder cancer cell lines, CYP1‐activity was undetectable/low in basal PORlo T24 and SCaBER cells and higher in the luminal POR over‐expressing RT4 and RT112 cells than in differentiated NHU cells, indicating that CYP‐function is related to differentiation status in bladder cancers. This study establishes POR as a predictive biomarker of metabolic potential. This has implications in bladder carcinogenesis for the hepatic versus local activation of carcinogens and as a functional predictor of the potential for MIBC to respond to prodrug therapies.
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影响因子：
3.9
作者：
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通讯作者：
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影响因子：
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DOI：
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