164 Aberration of a cell adhesion molecule, CADM1, and its pathological or biological significance in urinary bladder cancer

Abstract

INTRODUCTION AND OBJECTIVES: Tumor suppressor CADM1 (cell adhesion molecule 1) belongs to the immunoglobulin-superfamily cell adhesion molecules (IgCAMs) and participates in cell-cell adhesion activity in various epithelia, including those of urinary bladder. On the other hand, CADM1 is frequently inactivated in a variety of human cancers chiefly by gene promoter methylation, especially in their advanced stages. In this study, we investigated possible involvement of CADM1 in bladder cancer. METHODS: CADM1 expression in 11 human bladder cancer cell lines was examined by RT-PCR analysis and western blotting analysis. The methylation status of the CADM1 gene promoter in bladder cancer cell lines was examined by pyrosequencing analysis. CADM1 expression in 147 human primary bladder cancers was examined by immunohistochemical analysis. Cadm1-deficient mice as well as the wild-type C57BL/6 mice were administrated 0.05% N-butyl-N(4-hydroxybutyl)nitrosamine (BBN), an established bladder carcinogen for mice, in the drinking water for 20 weeks. Any human examination was conducted according to the protocol approved by the research ethics committee of Graduated School of Medicine, The University of Tokyo. RESULTS: CADM1 expression was absent or greatly reduced in 6 of 11 human bladder cancer cell lines. The promoter methylation of the CADM1 gene was observed in 4 of those 6 cell lines. CADM1 was expressed along the cell membrane in normal urothelium of human bladder. On the other hand, membranous expression was lost or altered in 92 (63%) of 147 primary bladder cancers. Loss or aberrant expression of CADM1 was significantly correlated with higher pT stages (pTa pT1 pT2-4), higher nuclear grade (G1-2 G3). Moreover, loss or aberrant expression was closely correlated with poor prognosis (P 0.001) and was an independent prognostic factor in multivariate analysis (P 0.021) in 112 patients treated with radical cystectomy. Administration of BBN developed invasive bladder cancers (pT2-4) at significantly higher incidence in Cadm1-deficient mice than in the wild-type mice (P 0.025). CONCLUSIONS: The disruption of CADM1 would be involved in the progression of bladder cancers, especially in the invasion and metastasis, and could provide a prognostic marker in invasive bladder cancer. Source of Funding: None