Splicing variants of carbonic anhydrase IX in bladder cancer and urine sediments

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• 作者：Francesca Malentacchi ; Ph.D.^a ; Serena Vinci ; M.D.^a ; Alessandro Della Melina ; M.D.^b ; Jitka Kuncova ; M.D.^c ; Donata Villari ; M.D.^b ; Gianluca Giannarini ; M.D.^c ; Gabriella Nesi ; M.D.^d ; Cesare Selli ; M.D.^c ; Claudio Orlando ; Ph.D.^a ; ^{c.orlando@dfc.unifi.it}
• 关键词：Hypoxia ; CAIX ; Alternative splicing ; Bladder cancer ; Urine sediment
• 刊名：Urologic Oncology ; Seminars and Original Investigations
• 出版年：2012
• 期刊代码：266_10781439
• 类别：med
• 出版时间：May-June, 2012
• 卷：30
• 期：3
• 页码：278-284
• 文件大小：833 K

摘要

Objective

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.

Materials and methods

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.

Results

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 鈮T2 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.

Conclusions

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.