Clinical Biochemistry, Department of Clinical Physiopathology, University of Florence, Florence, Italy.
Urol Oncol. 2012 May-Jun;30(3):278-84. doi: 10.1016/j.urolonc.2010.05.009. Epub 2010 Sep 26.
In human cancers, carbonic anhydrase IX (CAIX) influences cell proliferation and tumor progression, maintaining intracellular and extracellular pH under hypoxic conditions. An alternative CAIX isoform, lacking of exons 8-9 (AS) and independent from the levels of hypoxia, was recently demonstrated in cancer cells. AS-CAIX competes with the full-length (FL) isoform in the regulation of the extracellular pH, mainly in a mild hypoxic status. In the present study, we evaluated mRNA expression of the 2 CAIX isoforms and their clinical relevance in bladder cancers and urine sediments.
We measured mRNA expression of FL- and AS-CAIX isoforms in tumor tissues and benign mucosa from 45 patients with bladder transitional cell carcinoma. The expression of the 2 isoforms was also measured in urine sediment of 81 bladder cancer patients and 93 control subjects.
Expression of FL-CAIX mRNA was lower than AS-CAIX in benign mucosa (P = 0.006) whereas in paired bladder cancers FL-CAIX mRNA was higher (P = 0.007). Consequently, the percentage of FL-CAIX in bladder cancers [median: 62.6%] was significantly higher than in benign mucosa [15.0%] (P < 0.0001). In the urinary sediments of bladder cancer patients FL-CAIX mRNA was significantly higher in comparison with normal controls (P = 0.003). FL-CAIX percentage appeared dramatically higher in urine sediments of bladder cancer patients [64.5%] in comparison with controls [7.5%] (P < 0.0001). In addition, FL-CAIX% was significantly different in sediments from pTa-pT1 and ≥ pT2 patients [51.5% and 91.7%, respectively] (P = 0.016). Stratification according tumor grade indicated that FL-CAIX% was significantly lower in G1 bladder cancers [33.3%] in comparison with G2-G3 [88.6%] (P = 0.005) The clinical sensitivity for FL-CAIX% in urine sediments was 0.93, with a 0.76 specificity. Using the same cut-off positive predictive value (PPV) was 0.78, whereas negative predictive value (NPV) was 0.93.
Our results seem to indicate that in bladder cancers and related urine sediments, FL-CAIX is the prevalent and is the most accurate clinically relevant variant surrogate of hypoxic stress.
在人类癌症中，碳酸酐酶 IX（CAIX）影响细胞增殖和肿瘤进展，在低氧条件下维持细胞内和细胞外的 pH 值。最近在癌细胞中发现了一种缺乏外显子 8-9（AS）的 CAIX 替代异构体，其独立于缺氧水平。AS-CAIX 与全长（FL）异构体一起在调节细胞外 pH 值方面竞争，主要在轻度低氧状态下。在本研究中，我们评估了 2 种 CAIX 异构体的 mRNA 表达及其在膀胱癌和尿沉淀物中的临床相关性。
我们测量了 45 例膀胱癌患者肿瘤组织和良性黏膜中 FL-和 AS-CAIX 异构体的 mRNA 表达。还测量了 81 例膀胱癌患者和 93 例对照者尿沉淀物中 2 种异构体的表达。
良性黏膜中 FL-CAIX mRNA 的表达低于 AS-CAIX（P = 0.006），而配对膀胱癌中 FL-CAIX mRNA 的表达更高（P = 0.007）。因此，膀胱癌中 FL-CAIX [中位数：62.6%]的百分比明显高于良性黏膜 [15.0%]（P < 0.0001）。在膀胱癌患者的尿液沉淀物中，FL-CAIX mRNA 明显高于正常对照者（P = 0.003）。与对照组 [7.5%]相比，膀胱癌患者尿液沉淀物中 FL-CAIX% [64.5%]明显升高（P < 0.0001）。此外，pTa-pT1 和≥pT2 患者尿液沉淀物中的 FL-CAIX% [分别为 51.5%和 91.7%]差异有统计学意义（P = 0.016）。根据肿瘤分级分层表明，G1 膀胱癌中 FL-CAIX% [33.3%]明显低于 G2-G3 [88.6%]（P = 0.005）。尿液沉淀物中 FL-CAIX%的临床灵敏度为 0.93，特异性为 0.76。使用相同的截断值阳性预测值（PPV）为 0.78，而阴性预测值（NPV）为 0.93。
我们的研究结果似乎表明，在膀胱癌及其相关尿沉淀物中，FL-CAIX 是最普遍和最准确的临床相关缺氧应激替代变体。
