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CA 9 (Carbonic Anhydrase IX)
Carbonic anhydrase IX (CA9, also known as membrane antigen MN) is a member of the carbonic anhydrase protein family. It is a transmembrane protein that consists of an N-terminal signal peptide, an extracellular proteoglycan-related domain and catalytic domain, a transmembrane segment, and a C-terminal intracellular tail. The major physiologic function for CA9 is to regulate pH by catalyzing the reversible hydration of carbon dioxide to carbonic acid, which subsequently decomposes to HCO3 and H3O. Primarily expressed in the gut, CA9 is ectopically up-regulated in many types of tumors, such as renal cell carcinoma, non-small cell lung cancer, breast cancer, and cervical cancer. One of the mechanisms underlying the over-expression of CA9 in tumor tissues is hypoxia. Under hypoxic conditions, the CA9 gene is induced by its upstream regulator, the hypoxia inducible factor (HIF)-1 transcription factor. CA9 facilitates the tumor cells to create an acidified local environment to promote growth and metastasis. Another mechanism governing the enhanced expression of CA9 in tumor tissues is the loss of the tumor suppressor gene, von Hippel0Lindau (VHL). Some experimentally evidence has shown that mutations in the VHL gene can lead to over-expression of CA9 in cancer cell lines. CA9 has also been found to have many connections with some signal transduction pathways. The tyrosine moiety of the intracellular tail of CA9 can be phosphorylated in an epidermal growth factor-dependent manner and the phosphorylated CA9 can interact with PI-3-kinase. Additionally, CA9 has been demonstrated to mediate cell adhesion. The expression of CA9 in tumor tissues is often correlated with aggressive phenotypes. Furthermore, CA9 as a therapeutic target has also been proposed.
The ectodomain of CA9 can be released in the extracellular milieu. The soluble form of CA9 has been detected in cell culture supernates as well as biological fluids, such as serum and urine. The metalloproteases, TNF-α-converting enzyme (TACE/ADAM117), is likely to regulate this process.
The CA IX immunoassay is a solid-phase ELISA designed to measure human CA IX in cell culture supernates, serum, plasma, and urine. This assay employs the quantitative sandwich enzyme immunoassay technique.
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