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  • Carbonic anhydrase (CA), a family of zinc metalloenzymes, can efficiently catalyze the reversible processes of hydration-dehydration of CO2 and HCO3−. Carbonic anhydrase 9 (CA9) is located on chromosome 9p12–13, which comprises 11 exons and encodes for the 459-amino-acidprotein. CA9 helps to keep a normal pH in tumor cells in a hypoxic microenvironment and allow tumor cell proliferation [pone.0082804-Chien1]. CA9, which is not expressed in most benign tissues, is abundant in many cancers including renal cancer, bladder cancer, oral cancer, lung cancer and uterine cancer and has been thought to be an endogenous marker for tumor hypoxia [pone.0082804-Ivanov1]. Single nucleotide polymorphism (SNP) is a variation in the DNA sequence that occurs when a nucleotide (A, T, C, or G) is changed in at least 1% of a certain population [pone.0082804-Chien1]. Previous study showed that SNP in the exon region of CA9 are associated with overall survival for metastatic renal cell carcinoma [pone.0082804-deMartino1] and gene-environment interactions of CA9 polymorphisms, smoking, and betel quid chewing might alter oral cancer susceptibility and metastasis [pone.0082804-Chien1]. One published report suggests a tripartite role of CA9 as a diagnostic, prognostic, and therapeutic molecular marker in bladder cancer [pone.0082804-Klatte1]. However, no reports focused on the association between CA9 gene polymorphisms and UCC. The present study investigated relationships between SNPs (rs2071676, rs3829078, and 376del393) in the exon and 3’-UTR (rs1048638) regions of the CA9 gene and the risk of UCC. The influences of these SNPs combined with tobacco consumption on clinicopathological characteristics of UCC were also evaluated. To our knowledge, this is the first study to demonstrate a significant association between CA9 gene polymorphisms and UCC.

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