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  • CA9 is abundant in cancers but not in most benign tissues. It helps tumor cells to survive and proliferate in a hypoxic condition [pone.0082804-deMartino1]. The expression of CA9 gene was markedly induced under hypoxic conditions in tumor cells and CA 9 may maintain extracellular acidic pH in microenvironment and help cancer cells grow and metastasize [pone.0082804-Ivanov1]. It was reported that CA9 as a marker of hypoxia and it is also associated with the tumor grade, metastasis and patients prognosis [pone.0082804-Klatte1]. CA9 expression is associated with poor prognosis in many human tumors, and may contribute to aggressive cancer phenotype [pone.0082804-Potter1]. In non-small cell lung cancer, the CA9 up-regulation occurs in highly hypoxic/necrotic regions of the tumors and CA9 expression is strongly associated with poor outcome through the mechanism of angiogenesis, apoptosis inhibition, and cell-cell adhesion disruption [pone.0082804-Giatromanolaki1]. In high risk, early stage cervical cancer, CA9 is an independent prognostic factor for both progression free survival and overall survival [pone.0082804-Liao1]. Furthermore, it was reported that high expression of CA9 was more frequent with advanced stage in several kinds of solid tumors including bladder cancer [pone.0082804-Koukourakis1]. In the present study, a significantly higher distribution frequency of Invasive tumor stage was exhibited in UCC patients with at least 1 polymorphic A allele of CA9 rs1048638 compared to those with the WT genotype ([pone-0082804-t003]). The rs1048638 polymorphism is known in the noncoding 3’-UTR, and as such may affect gene expression through microRNA-targeting sequences. However, the expression and function of CA9 which are affected by this SNP are still unconfirmed. Detailed relevant mechanisms may warrant further studies.


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