Plakins are a family of cytoskeletal proteins that maintain cytoskeletal integrity and are often associated with intermediate filaments and desmosomal adhesion complexes. Less studied is their mediation of signalling pathways that can regulate stress response, cellular growth, migration, invasion and differentiation. Non-cancerous diseases of the skin, striated muscle and nervous tissue are associated with abnormal or loss of plakin proteins. As plakins are essential to epithelial cell structure, we suggest that plakins may play a role in epithelial ovarian cancer progression and recurrence.
Here we investigate the prevalence of plakins in epithelial ovarian cancer, particularly plectin (PLEC), periplakin (PPL) and envoplakin (EVPL). Using immunohistochemistry we found consistent patterns of expression of PLEC, PPL and EVPL in serous ovarian tumours. These three proteins were consistently highly expressed in benign ovarian tissues and the expression was sustained in low-grade serous ovarian tumours (WHO type I). However, PLEC and PPL were expressed at low levels in high-grade serous ovarian cancer (WHO type II) compared to benign/low-grade tumours, with the expression of EVPL remaining unchanged. The expression of plakins was mainly confined to cell membranes and moderate cytoplasmic staining was observed in certain cases. There was no change in the protein-expression pattern of plakins between benign/low-grade and high-grade tumours.
The connection between plakin expression and the presence of epithelial-mesenchymal transition (EMT) markers was explored in ovarian tumours and ovarian cancer cell lines. PPL expression was found to be expressed consistently higher in cell lines with an epithelial phenotype and lower in cell lines with a more mesenchymal and aggressive phenotype. High-grade cases with high levels (above median) of PLEC and PPL had correlating low expression of N-cadherin (NCAD) in these tumours, and frequently low VIM expression. Analysis of TCGA data revealed amplification of the PLEC gene significantly improved both progression free and overall survival in patients with high-grade ovarian tumours.