Article Abstract

Expression of the desmosome-related molecule periplakin is associated with advanced stage and poor prognosis of esophageal squamous cell carcinoma

Authors: Kazuhiko Yamada, Teruki Hagiwara, Fumika Inazuka, Takuhito Sezaki, Toru Igari, Chizu Yokoi, Kyoko Nohara, Satoshi Yamashita, Taeko Dohi, Yuki I. Kawamura

Abstract

Background: Our previous report showed that periplakin (PPL), a member of the plakin family of proteins, was expressed in all the normal esophageal squamous cells, except the Ki67+ basal cell layer; however, PPL-negative cells were observed in esophageal squamous cell carcinoma (ESCC) tissue samples and the proportion of PPL-positive areas in tumors showed considerable variation. In this study, we analyzed the relationships between PPL expression in tumors and the clinicopathological features of ESCC. Methods: PPL expression was evaluated by immunostaining ESCC samples from 70 patients who underwent surgery and we classified the samples into PPL-negative and PPL-positive groups based on the proportion of PPL-positive areas in tumors, and the relationships among PPL expression, clinical features, and the ESCC prognosis were analyzed. ESCC cell line KYSE270 cells were stably transfected with the PPL expression vector and their growth was assessed by colony formation assay and subcutaneous xenografts in athymic mice. Results: As found in our previous study, decreased PPL staining intensity was observed in all of the cancer tissues analyzed, compared with that observed in paired normal esophageal mucosae; however, the PPL-positive group (the percentage of PPL-positive tumor cells was >20% on immunostaining) exhibited positive associations with the pT classification (larger primary tumor) (P=0.029), pN classification (lymph node metastasis) (P=0.0462), and advanced stages of cancer (P=0.0253). High PPL expression was observed in all of 26 lymph node metastases analyzed. Furthermore, patients with PPL-positive tumors showed poor postoperative prognosis compared to those with PPL-negative ones. Forced expression of PPL in the KYSE270 ESCC cell line induced a stratified structure and colony formation. In addition, PPL-transfected cells formed larger tumors in nude mice than mock-transfected cells, suggesting that relatively high PPL expression in tumors may facilitate cell-cell adhesion by desmosome formation and eventual cell growth in vivo. Conclusions: PPL expression was generally reduced in ESCC compared with paired non-cancer tissue; however, relatively high levels of PPL expression in tumors correlated with tumor progression, lymph node metastasis, advanced stage cancer, and a poor prognosis.