Unconjugated
Intraductal papillary mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasia (PanINs) are important premalignant lesions of pancreatic cancer. Ezrin is a member of the ezrin, radixin, and moesin protein family and acts as a cross-linker between the plasma membrane and the actin cytoskeleton. We investigated the roles of ezrin during carcinogenesis in IPMN and invasive ductal carcinoma and examined whether ezrin was a prognostic factor. We examined ezrin and phosphorylated ezrin (p-ezrin) expression in 131 IPMNs, 47 PanINs, and 59 invasive ductal carcinomas by immunohistochemical staining. Ezrin and p-ezrin (tyr354) expressions were significantly higher in IPMN with an associated invasive carcinoma, compared with those in IPMN with high-grade dysplasia (P = .03 and P = .0007, respectively). In all grades of PanINs, ezrin and p-ezrin (tyr353) were highly expressed. In patients with invasive ductal carcinoma, the presence of PanIN-2 or PanIN-3 was significantly correlated with positive ezrin and p-ezrin (tyr353) expression of the invasive ductal carcinoma component (P = .01 and P = .0004). The negative p-ezrin (tyr353) expression group of invasive ductal carcinoma showed a significantly worse prognosis than did the positive p-ezrin (tyr353) expression group by survival analysis (P = .04) and was a statistically significant adverse prognostic factor by both univariate and multivariate analyses (P = .048 and P = .015). Ezrin phosphorylation sites differ between the developments of IPMN and PanIN. Although p-ezrin (tyr354) expression in IPMNs is associated with tumor invasion, p-ezrin (tyr353) expression in invasive ductal carcinoma plays an important role not in tumor invasion and metastasis but in the early development of PanINs.
It has been suggested that ezrin activation plays a key role in the regulation of cancer metastasis. In this study, we immunohistochemically investigated the expression patterns of total ezrin and its two phosphorylated forms, pEzrin(- Thr567) and pEzrin(- Tyr353), in 66 samples of invasive pancreatic carcinomas and 11 samples of normal pancreas tissues. Positive expressions of ezrin and pEzrin(- Thr567) were detected in most PDAC tissues, significantly higher than that of pEzrin(- Tyr353). Furthermore, overexpression of pEzrin(- Tyr353) in pancreatic cancers was associated with positive lymph node metastasis, less differentiation, pAkt overexpression, and shorter survival times. pEzrin(- Tyr353) may be a potent prognosis predictor for pancreatic cancer.