Carbonic anhydrase IX is a marker of hypoxia and correlates with higher Gleason scores and ISUP grading in prostate cancer.
Carbonic anhydrase IX is a marker of hypoxia and correlates with higher Gleason scores and ISUP grading in prostate cancer.
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DOI：
10.1186/s13000-016-0495-1
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发表时间：
2016-05-25
影响因子：
2.6
通讯作者：
Tarantini F
中科院分区：
文献类型：
--
作者：
Ambrosio MR;Di Serio C;Danza G;Rocca BJ;Ginori A;Prudovsky I;Marchionni N;Del Vecchio MT;Tarantini F
碳酸酐酶IX是α-碳酸酐酶的成员，其优先在实体瘤中表达。它能够使碳酸氢盐转运穿过质膜，中和细胞内pH值，并赋予癌细胞在缺氧/酸性微环境中的生存优势。癌组织中碳酸酐酶IX的过表达受缺氧诱导因子1α-介导的转录调节，该酶被认为是肿瘤缺氧和预后不良的标志物。碳酸酐酶IX在前列腺癌中的作用尚未完全阐明，并且关于这种酶是否在缺氧的前列腺癌组织中过表达的争议已经出现。我们分析了碳酸酐酶IX和缺氧诱导因子1α在两个前列腺癌细胞系，LNCaP和PC-3，并在110个癌症活检，通过蛋白质印迹和免疫细胞/组织化学的表达。在LNCaP和PC-3细胞中，碳酸酐酶IX主要是细胞质/细胞核，具有非常有限的膜定位。缺氧时细胞核染色增强。当我们分析人前列腺癌活检组织中碳酸酐酶IX的表达时，我们发现蛋白质染色与缺氧诱导因子1α、Gleason模式和评分以及国际泌尿病理学会提出的前列腺癌新分级系统呈正相关。再次，碳酸酐酶IX主要是在低级别癌细胞质，而在高级别肿瘤强烈表达在肿瘤细胞的细胞核。碳酸酐酶IX表达水平与前列腺癌侵袭性的主要临床病理特征之间存在相关性。在前列腺癌组织中，碳酸酐酶IX和缺氧诱导因子1α之间存在统计学显著相关性，这表明该酶是肿瘤缺氧的可靠标志物。此外，碳酸酐酶IX的表达与前列腺癌的分级和分期以及预后呈正相关，这表明该蛋白可能是该疾病的独立预测因子。低氧癌细胞中酶的核转位可能是肿瘤向不太有利的表型的生物学转换的缩影。
Carbonic anhydrase IX is a member of α-carbonic anhydrases that is preferentially expressed in solid tumors. It enables bicarbonate transport across the plasma membrane, neutralizing intracellular pH and conferring to cancer cells a survival advantage in hypoxic/acidic microenvironments. Overexpression of carbonic anhydrase IX in cancer tissues is regulated by hypoxia inducible factor 1α − mediated transcription and the enzyme is considered a marker of tumor hypoxia and poor outcome. The role of carbonic anhydrase IX in prostate cancer has not been fully clarified and controversy has arisen on whether this enzyme is overexpressed in hypoxic prostate cancer tissues. We analyzed the expression of carbonic anhydrase IX and hypoxia inducible factor 1α in two prostate cancer cell lines, LNCaP and PC-3, and in 110 cancer biopsies, by western blotting and immunocyto/histochemistry. In LNCaP and PC-3 cells, carbonic anhydrase IX was mostly cytoplasmic/nuclear, with very limited membrane localization. Nuclear staining became stronger under hypoxia. When we analyzed carbonic anhydrase IX expression in human prostate cancer biopsies, we found that protein staining positively correlated with hypoxia inducible factor 1α and with Gleason pattern and score, as well as with the novel grading system proposed by the International Society of Urological Pathology for prostate cancer. Once more, carbonic anhydrase IX was mainly cytoplasmic in low grade carcinomas, whereas in high grade tumors was strongly expressed in the nucleus of the neoplastic cell. An association between carbonic anhydrase IX expression level and the main clinic-pathological features involved in prostate cancer aggressiveness was identified. There was a statistically significant association between carbonic anhydrase IX and hypoxia inducible factor 1α in prostate cancer tissues, that identifies the enzyme as a reliable marker of tumor hypoxia. In addition, carbonic anhydrase IX expression positively correlated with prostate cancer grading and staging, and with outcome, suggesting that the protein may be an independent prognosticator for the disease. The nuclear translocation of the enzyme in hypoxic cancer cells may epitomize a biological switch of the tumor towards a less favorable phenotype.