Tumor-specific downregulation and methylation of the CDH13 (H-cadherin) and CDH1 (E-cadherin) genes correlate with aggressiveness of human pituitary adenomas.
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.
Qian
Zhi Rong
ZR
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
Sano
Toshiaki
T
Yoshimoto
Katsuhiko
K
Asa
Sylvia L
SL
Yamada
Shozo
S
Mizusawa
Noriko
N
Kudo
Eiji
E
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
D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins; C099972:H-cadherin