Abstract
Periplakin (PPL), a member of the plakin family of proteins that localizes to desmosomes and intermediate filaments, is downregulated in human esophageal squamous cell carcinoma (ESCC). Little is known, however, about the molecular mechanism underlying the regulation of PPL expression and the contribution of PPL loss to the malignant property of the cancer is unclear. We demonstrated that PPL mRNA expression was significantly reduced in ESCC tissues compared with that in normal tissues. Therefore, we hypothesized that CpG hypermethylation is the cause of the downregulation of PPL. Bisulfite-pyrosequencing of 17 cases demonstrated that the frequency of PPL methylation was higher in ESCC tissues than in normal tissues. When human ESCC cell lines were treated with 5-aza-2′-deoxycytidine (5-aza-dC), a DNA-methyltransferase inhibitor, PPL transcription was induced. Human KYSE270 ESCC cells do not stratify under ordinary culture conditions and rarely produce desmosomes; however, the forced expression of PPL promoted cell stratification. PPL induction also promoted adhesion to extracellular matrix but delayed cell migration. The abundance of desmosome-like structures was greatly increased in PPL transfectant as determined by transmission electron microscopy. Very low expression of another desmosome protein EVPL in ESCC, even in PPL transfectant, also supported the significant role of PPL in desmosome formation and cell stratification. Our results first indicate that the downregulation of PPL mediated by DNA hypermethylation, which may play an important role in the loss of ESCC stratification and likely in metastatic phenotype.
Highlights
To transfer various types of food to the stomach, the esophageal mucosa requires resistance to mechanical stress
Forced PPL expression induced epithelial cell stratification and the piling up of cancer cells To further understand the significance of PPL defects in esophageal squamous cell carcinoma (ESCC), we investigated the effect of forced PPL expression in the ESCC cell line KYSE270
We found that PPL, a desmosome protein, was one of the targets of aberrant DNA hypermethylation in ESCC
Summary
To transfer various types of food to the stomach, the esophageal mucosa requires resistance to mechanical stress. One of the mechanisms supporting such resistance is the stratified structure of the squamous epithelial cells, which have many spines that intermingle with each other through dense desmosomes. Periplakin (PPL) is a 195kDa, membrane-associated protein and a member of the plakin protein family, which comprises desmoplakin, envoplakin (EVPL), plectin, and bullous pemphigoid antigen 1. Plakin family proteins connect cytoskeleton elements to form intercellular junction complexes such as desmosomes [1, 2]. PPL is expressed in keratinized and nonkeratinized epithelial cells of the epidermis, the urinary bladder, and the oral, esophageal, and cervical mucosa [1]. PPL forms stable heterodimers with EVPL that localize to the desmosomes, the interdesmosomal plasma membrane and intermediate filaments, and the plasma membrane in a manner that depends on the PPL N-terminus [3]
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