RRC ID 38456
Author Nakamura J, Kitajima Y, Kai K, Hashiguchi K, Hiraki M, Noshiro H, Miyazaki K.
Title Expression of hypoxic marker CA IX is regulated by site-specific DNA methylation and is associated with the histology of gastric cancer.
Journal Am J Pathol
Abstract The hypoxic marker carbonic anhydrase (CA) IX has been recognized as a tumor-associated protein and is essential for cancer development. However, because CA IX expression does not always correlate with hypoxia, its regulatory mechanism remains unclear. The objective of the present study was to clarify the role and regulation of CA IX expression in gastric cancer. The immunohistochemical expression of CA IX and hypoxia-inducible factor-1α was assessed in 77 patients with gastric cancer. A methylation-sensitive restriction enzyme method was used to quantify site-specific methylation at -74 bp in the CA9 promoter in tissue from patients with gastric cancer and in corresponding normal tissue. CA9 expression in cell lines was strongly dependent on methylation status but not hypoxic stimuli. In tissue from patients with gastric cancer, the quantity of methylation was significantly correlated with the protein expression (P = 0.003). Moreover, the methylation value was significantly lower in intestinal-type compared with diffuse-type cancer (P = 0.003). Compared with normal mucosa, intestinal-type cancer demonstrated significant hypomethylation, whereas diffuse-type cancer exhibited hypermethylation. In conclusion, expression of CA IX in gastric cancer is predominantly regulated by methylation of a single CpG rather than by hypoxia. Furthermore, epigenetic alterations in CA9 differ between the intestinal and diffuse types of gastric cancer.
Volume 178(2)
Pages 515-24
Published 2011-2-1
DOI 10.1016/j.ajpath.2010.10.010
PII S0002-9440(10)00103-3
PMID 21281785
PMC PMC3069889
MeSH Adult Aged Aged, 80 and over Antigens, Neoplasm / genetics* Antigens, Neoplasm / metabolism Azacitidine / pharmacology Azacitidine / therapeutic use Carbonic Anhydrase IX Carbonic Anhydrases / genetics* Carbonic Anhydrases / metabolism Cell Hypoxia / drug effects Cell Hypoxia / genetics Cell Line, Tumor DNA Methylation / drug effects DNA Methylation / genetics* Female Gene Expression Regulation, Neoplastic* / drug effects Humans Hydroxamic Acids / pharmacology Hydroxamic Acids / therapeutic use Hypoxia-Inducible Factor 1, alpha Subunit / metabolism Immunohistochemistry Kaplan-Meier Estimate Male Middle Aged Promoter Regions, Genetic / genetics Stomach Neoplasms / drug therapy Stomach Neoplasms / enzymology Stomach Neoplasms / genetics* Stomach Neoplasms / pathology*
IF 3.491
Times Cited 26
Human and Animal Cells