Overexpression of enhancer of zeste homolog 2 and MUC1 may be related to malignant behaviour in intraductal papillary neoplasm of the bile duct

Aims: Intraductal papillary neoplasm of the bile duct (IPNB) usually has a favourable prognosis, but occasionally is associated with invasive carcinoma. Overexpression of the polycomb group protein enhancer of zeste homolog 2 (EZH2) is involved in the progression of malignant tumours. In this study, we examined the significance of EZH2 expression in IPNB and its association with clinicopathological features and the expression of p16INK4a, p53 and mucin core proteins. Methods and results: We examined immunohistochemically the expression of EZH2, p16INK4a, MUC mucin core proteins and p53 in 15 patients with IPNB without invasion, including the cystic variant [male/female ratio (M/F) = 9/6], and in 19 with IPNB associated with invasive carcinoma (M/F = 13/6). The expression levels of EZH2, p53 and MUC1 were significantly lower (P < 0.01), and of MUC6 were significantly higher (P < 0.05), in IPNB without invasion than in IPNB with invasion. Expression of EZH2 was significantly correlated with expression of MUC1 (P < 0.01) and inversely correlated with expression of MUC6 (P < 0.05). In cholangiocarcinoma cells (HuCTT-1 and TFK-1), knockdown of EZH2 and MUC1 by small interfering RNA decreased invasion and proliferation, whereas knockdown of MUC6 increased invasion. Conclusions: Overexpression of EZH2 may be associated with malignant behaviour in IPNB in parallel with up-regulated MUC1 expression and down-regulated MUC6 expression.