Loss of T-Cadherin (CDH13, H-Cadherin) Expression in Cutaneous Squamous Cell Carcinoma

• Published in: Laboratory investigation Vol. 82; no. 8; pp. 1023 - 1029
• Main Authors: Takeuchi, Tamotsu, Liang, Sheng-Ben, Matsuyoshi, Norihisa, Zhou, Shuxia, Miyachi, Yoshiki, Sonobe, Hiroshi, Ohtsuki, Yuji
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.08.2002; Nature Publishing; Nature Publishing Group
• Subjects: Biological and medical sciences; Cadherins - biosynthesis; Cadherins - genetics; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Dermatology; DNA Methylation; Down-Regulation; Gene Deletion; Humans; Medical sciences; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Tumors of the skin and soft tissue. Premalignant lesions; Human; Immunohistochemistry; Pathology; Skin disease; Squamous cell carcinoma; Loss of heterozygosity; Skin; Malignant tumor; Molecular biology; Cadherin; Carcinogenesis
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1097/01.LAB.0000025391.35798.F1

We previously reported that T-cadherin (CDH13, H-cadherin), a unique cadherin molecule, was expressed on the basal cell layer in normal murine and human epidermis. In the present study, T-cadherin expression in archival human skin specimens comprising a spectrum of human squamous cell neoplasia was investigated. T-cadherin expression was observed in both normal epidermal basal cells and adnexal epithelial cells of formalin-fixed and paraffin-embedded tissue sections. Western immunoblotting also revealed that mature T-cadherin protein was expressed in cultured human skin tissue equivalent. Atypical keratinocytes in 27 of 53 specimens of actinic keratosis and 23 of 30 specimens of Bowen's disease expressed T-cadherin. In contrast, T-cadherin was focally expressed in 6 of 56 invasive cutaneous squamous cell carcinomas. To explore the molecular mechanism of down-regulation of T-cadherin expression in invasive squamous cell carcinoma, loss of heterozygosity, genetic alternations, and methylation status in the 5′ region of the T-cadherin gene were investigated. Loss of heterozygosity at intron 1 of the T-cadherin gene was observed in 8 of 28 informative cases of invasive squamous cell carcinoma. Although no structural genomic alternations were found by sequence analysis, aberrant promoter methylation of the T-cadherin gene was found in 12 of 28 invasive squamous cell carcinomas. T-cadherin expression was restored in cultured A431 cells, in which aberrant methylation was found by treatment with the demethylating agent 5′-aza-2-deoxycytidine. These findings suggest that a combination of deletion and aberrant methylation of the T-cadherin gene may play a role in loss of gene expression in a considerable number of invasive cutaneous squamous cell carcinomas.