title: P-cadherin controls the differentiation of oral keratinocytes by regulating cytokeratin 1/10 expression via C/EBP-beta-mediated signaling.
abstract: P-cadherin belongs to the family of Ca(2+)-dependent homophilic glycosylated cell adhesion molecules. In the normal oral epithelium it shows a strong expression in the basal cell layer which gradually decreases in the suprabasal cell layers. The exact role of P-cadherin during the development and homeostasis of the oral epithelium has not been elucidated, yet. Here, we show for the first time that P-cadherin controls differentiation by regulating cytokeratin (CK) 1/10 expression in primary oral keratinocytes (POK) from normal, but interestingly not in POKs from oral squamous cell carcinoma (OSCC) tissue. SiRNA knockdown of P-cadherin in normal POKs revealed a strong upregulation of CK1/10 expression on mRNA and protein level. In contrast, E-cadherin knockdown in normal oral keratinocytes did not show any influence on CK1/10 expression. Moreover, in comparison with normal control keratinocytes normal oral keratinocytes with reduced P-cadherin expression displayed an enhanced expression and a stronger nuclear staining of C/EBP-beta, a well-known regulator of CK1/10 expression in keratinocytes. Furthermore, after P-cadherin knockdown in normal POKs the promoter activity of a C/EBP-responsive luciferase construct was significantly higher than in normal POKs with regular P-cadherin expression. Additionally, we noticed a proliferation advantage in normal oral keratinocytes in contrast to keratinocytes with diminished P-cadherin expression. However, the inverted effect was seen in tumor derived primary oral keratinocytes. In summary, we show that P-cadherin contributes to the keratinocyte differentiation in the oral epithelium by influencing the CK1 and CK10 expression via C/EBP-beta-mediated signaling in normal but not in tumor derived oral keratinocytes from OSCC patients.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Bauer
authors.forename: Martin
authors.initials: M
authors.lastname: Gosau
authors.forename: Anja
authors.initials: A
authors.lastname: Bosserhoff
authors.forename: Torsten
authors.initials: T
authors.lastname: Reichert
authors.forename: Richard
authors.initials: R
authors.lastname: Bauer
mesh_terms: D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D007633:Keratins / Q000235:genetics* / Q000378:metabolism; D009061:Mouth Mucosa / Q000166:cytology*; D009062:Mouth Neoplasms / Q000473:pathology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D015820:Cadherins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D007633:Keratins