Expression of exportin 1 (XPO1/CRM1) in pancreatic adenocarcinoma.

Abstract

327 Background: Exportin 1 (XPO1/CRM1) is a nuclear export chaperone that mediates the nuclear export of several proteins that are essential to growth regulation and tumor suppression. It was found to be overexpressed in several types of human malignancies and overexpression was found to be associated with poor prognosis. Pancreatic adenocarcinoma (PAC) is associated with very poor survival and currently has no effective treatment. Selective inhibitors of nuclear export are currently undergoing phase I and II clinical trials in hematologic malignancies and solid tumors. The aim of this study was to determine the expression of XPO1/CRM1 in pancreatic adenocarcinoma (PAC) and its relation to survivin expression and proliferative activity as determined by the S-phase fraction (SPF). Methods: Sections of tissue microarray containing 77 formalin fixed and paraffin embedded human PAC were stained by immunohistochemistry (IHC) using monoclonal antibodies to XPO1/CRM1, survivin, and for Cyclin A. The levels of XPO1/CRM1 and survivin expression in tumor cells and the S-phase fraction (SPF) were determined using a quantitative digital image analysis solution (OTMIAS). Results: Sixty-six of the 77 (86%) cases were positive for XPO1/CRM1, with the mean expression value ranging from 0.3 to 53 units and the median ranging from 0.3 to 45 units. There was significant correlation between the mean and median expression values of XPO1/CRM1 in tumor cells with the mean and median values of expression of survivin (p < 0.001). Moreover, the mean and median XPO1/CRM1 expression levels in tumor cells correlated significantly with SPF (p = 0.005). Conclusions: XPO1/CRM1 is expressed in a significant proportion of PAC, and increased expression correlates with both survivin expression and increased proliferative activity, suggesting that selective inhibitors of nuclear export may be effective against PAC.