title: Tumor-specific downregulation and methylation of the CDH13 (H-cadherin) and CDH1 (E-cadherin) genes correlate with aggressiveness of human pituitary adenomas.
abstract: The gene products of CDH13 and CDH1, H-cadherin and E-cadherin, respectively, play a key role in cell-cell adhesion. Inactivation of the cadherin-mediated cell adhesion system caused by aberrant methylation is a common finding in human cancers, indicating that the CDH13 and CDH1 function as tumor suppressor and invasion suppressor genes. In this study, we analyzed the expression of H-cadherin mRNA and E-cadherin protein in 5 normal pituitary tissues and 69 primary pituitary adenomas including all major types by quantitative real-time RT-PCR (qRT-PCR) and immunohistochemistry, respectively. Reduced expression of H-cadherin was detected in 54% (28/52) of pituitary tumors and was significantly associated with tumor aggressiveness (P<0.05). E-cadherin expression was lost in 30% (21 of 69) and significantly reduced in 32% (22 of 69) of tumors. E-cadherin expression was significantly lower in grade II, III, and IV than in grade I adenomas (P=0.015, P=0.029, and P=0.01, respectively). Using methylation-specific PCR (MSP), promoter hypermethylation of CDH13 and CDH1 was detected in 30 and 36% of 69 adenomas, respectively, but not in 5 normal pituitary tissues. Methylation of CDH13 was observed more frequently in invasive adenomas (42%) than in non-invasive adenomas (19%) (P<0.05) and methylation of CDH1 was more frequent in grade IV adenomas compared with grade I adenomas (P<0.05). Methylation of either CDH13 or CDH1 was identified in 35 cases (51%) and was more frequent in grade IV invasive adenomas than in grade I non-invasive adenomas (P<0.05 and P<0.05, respectively). Downregulation of expression was correlated with promoter hypermethylation in CDH13 and CDH1. In conclusion, the tumor-specific downregulation of expression and methylation of CDH13 and CDH1, alone or in combination, may be involved in the development and invasive growth of pituitary adenomas.
authors.affiliation: Department of Human Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Japan. zrqian@basic.med.tokushima-u.ac.jp
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sano
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yoshimoto
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
authors.forename: Shozo
authors.initials: S
authors.lastname: Yamada
authors.forename: Noriko
authors.initials: N
authors.lastname: Mizusawa
authors.forename: Eiji
authors.initials: E
authors.lastname: Kudo
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000473:pathology*; D000328:Adult; D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D019175:DNA Methylation; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010911:Pituitary Neoplasms / Q000235:genetics / Q000473:pathology*; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins; C099972:H-cadherin