Carbonic anhydrase 9 (CA9/CAIX) is an enzyme that in humans is encoded by the CA9gene.
Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. They show extensive diversity in tissue distribution and in their subcellular localization. CAIX is a transmembrane protein and is a tumor-associated carbonic anhydrase isoenzyme. It is over-expressed in VHL mutated clear-cell renal cell carcinoma (ccRCC) and hypoxic solid tumors, but is low-expressed in normal kidney and most other normal tissues. It may be involved in cell proliferation and transformation. This gene is mapped to 9p13-p12.
CAIX has been licensed by the Dendreon Corporation. It is under development as a target for Autologous Cellular Immunotherapy. Product candidates targeted at CA9 are in preclinical development for the treatment of kidney, colon, and cervical cancer.
CAIX is considered to be one of the best cellular biomarkers of hypoxia. Furthermore, recent studies examining the association between CAIX levels and various clinicopathological outcomes suggest that CAIX expression may also be a valuable prognostic indicator for overall survival. Antibodies against CAIX serve as excellent biomarkers of hypoxic regions in many solid tumors.
^Opavsky R, Pastorekova S, Zelnik V, Gibadulinova A, Stanbridge EJ, Zavada J, Kettmann R, Pastorek J (Sep 1996). "Human MN/CA9 gene, a novel member of the carbonic anhydrase family: structure and exon to protein domain relationships". Genomics33 (3): 480–7. doi:10.1006/geno.1996.0223. PMID8661007.
^Nakagawa Y, Uemura H, Hirao Y, Yoshida K, Saga S, Yoshikawa K (Dec 1998). "Radiation hybrid mapping of the human MN/CA9 locus to chromosome band 9p12-p13". Genomics53 (1): 118–9. doi:10.1006/geno.1998.5483. PMID9787087.
^Kirkpatrick JP, Rabbani, ZN, Bentley RC, Hardee ME, Karol S, Meyer J, Oosterwijk E, Havrilesky L, Secord AA, Vujaskovic Z, Dewhirst MW, Jones EL (Feb 2008). “Elevated CAIX Expression is Associated with an Increased Risk of Distant Failure in Early-Stage Cervical Cancer”. Biomark Insights 3:45-55.
Nishimori I, Onishi S (2001). "Carbonic anhydrase isozymes in the human pancreas.". Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver33 (1): 68–74. PMID11303978.
Pastorek J, Pastoreková S, Callebaut I, et al. (1994). "Cloning and characterization of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segment.". Oncogene9 (10): 2877–88. PMID8084592.
Závada J, Závadová Z, Pastoreková S, et al. (1993). "Expression of MaTu-MN protein in human tumor cultures and in clinical specimens.". Int. J. Cancer54 (2): 268–74. doi:10.1002/ijc.2910540218. PMID8486430.
Pastoreková S, Parkkila S, Parkkila AK, et al. (1997). "Carbonic anhydrase IX, MN/CA IX: analysis of stomach complementary DNA sequence and expression in human and rat alimentary tracts.". Gastroenterology112 (2): 398–408. doi:10.1053/gast.1997.v112.pm9024293. PMID9024293.
Saarnio J, Parkkila S, Parkkila AK, et al. (1998). "Immunohistochemistry of carbonic anhydrase isozyme IX (MN/CA IX) in human gut reveals polarized expression in the epithelial cells with the highest proliferative capacity.". J. Histochem. Cytochem.46 (4): 497–504. PMID9524195.
Kivelä AJ, Parkkila S, Saarnio J, et al. (2001). "Expression of transmembrane carbonic anhydrase isoenzymes IX and XII in normal human pancreas and pancreatic tumours.". Histochem. Cell Biol.114 (3): 197–204. PMID11083462.
Wingo T, Tu C, Laipis PJ, Silverman DN (2001). "The catalytic properties of human carbonic anhydrase IX.". Biochem. Biophys. Res. Commun.288 (3): 666–9. doi:10.1006/bbrc.2001.5824. PMID11676494.
Kivela AJ, Saarnio J, Karttunen TJ, et al. (2001). "Differential expression of cytoplasmic carbonic anhydrases, CA I and II, and membrane-associated isozymes, CA IX and XII, in normal mucosa of large intestine and in colorectal tumors.". Dig. Dis. Sci.46 (10): 2179–86. doi:10.1023/A:1011910931210. PMID11680594.
Koukourakis MI, Giatromanolaki A, Sivridis E, et al. (2002). "Hypoxia-regulated carbonic anhydrase-9 (CA9) relates to poor vascularization and resistance of squamous cell head and neck cancer to chemoradiotherapy.". Clin. Cancer Res.7 (11): 3399–403. PMID11705854.
Grabmaier K, de Weijert M, Uemura H, et al. (2002). "Renal cell carcinoma-associated G250 methylation and expression: in vivo and in vitro studies.". Urology60 (2): 357–62. doi:10.1016/S0090-4295(02)01711-9. PMID12137853.
Kaluz S, Kaluzová M, Chrastina A, et al. (2002). "Lowered oxygen tension induces expression of the hypoxia marker MN/carbonic anhydrase IX in the absence of hypoxia-inducible factor 1 alpha stabilization: a role for phosphatidylinositol 3'-kinase.". Cancer Res.62 (15): 4469–77. PMID12154057.
Swinson DE, Jones JL, Richardson D, et al. (2003). "Carbonic anhydrase IX expression, a novel surrogate marker of tumor hypoxia, is associated with a poor prognosis in non-small-cell lung cancer.". J. Clin. Oncol.21 (3): 473–82. doi:10.1200/JCO.2003.11.132. PMID12560438.
Bui MH, Seligson D, Han KR, et al. (2003). "Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy.". Clin. Cancer Res.9 (2): 802–11. PMID12576453.