[1599] Up-Regulation of Prion Protein Associated with K-Ras Mutation in Pancreatic Ductal Adenocarcinoma

C Kletecka, Q Li, W Xin, L Zhou. University Hospitals Case Medical Center, Cleveland, OH

Background: Mutations of the K-Ras oncogene are the most common genetic alteration in human pancreatic cancer. However, the mechanism by which the activation of the Ras signaling promotes tumor growth and metastasis remains to be fully elucidated. A recent study shows that prion protein (PrP) is over-expressed in a subgroup (41%) of human pancreatic ductal adenocarcinomas (PDAC), and its expression confers a poor prognosis. It also shows that PrP confers a growth advantage and contributes to the invasiveness of PDAC by binding with filamin A (FLNa), a cellular integrator of mechanics and signaling. In this study, we investigated the relationship between PrP and k-RAS mutation in PDAC.
Design: K-Ras mutation analysis was performed on paraffin embedded tissue blocks including 8 normal human pancreatic tissues and 28 human PDAC specimens, using TrimGen's K-Ras Mutector Detection Kit. K-Ras mutation signals were enriched by the Shifted Termination Assay technology and analyzed by fragment analysis on the ABI 3130 Genetic Analyzer. Immunohistochemistry was performed using monoclonal antibody specific for PrP.
Results: K-Ras mutation was identified in one normal human pancreatic specimen. Among 28 PDAC specimens, K-Ras mutation was identified in 19 cases (67.9%). No K-Ras mutation was identified in the resected normal peripheral pancreatic tissue of the corresponding PDAC specimen. Fifteen PDAC specimens have up-regulation of PrP by immunohistochemistry, showing focal or diffuse strong (3+) positive staining of infiltrative PDAC cells. PrP up-regulation is present in 13 of K-Ras mutation-positive PDAC specimens (68.4%). In comparison, PrP up-regulation is only found in 2 K-Ras mutation-negative specimens (22.2%) (p < 0.05).

PrP Expression Status and K-Ras Mutation in PDAC
K-Ras (+)K-Ras (-)Total
PrP (+)13215
PrP (-)6713
% of PrP (+)68.4%22.2%53.6%

Conclusions: Our studies have identified a strong association between K-Ras mutation and PrP up-regulation in human PDAC. Because K-Ras mutation is an earlier event in the progression of the pancreatic cancer than PrP up-regulation, these findings suggest that K-Ras mutation may promote pancreatic cancer growth by up-regulation of PrP. Further understanding the mechanism of PrP in conferring pancreatic cancer aggressiveness will lead to novel therapeutic options for treatment of this deadly disease.
Category: Liver & Pancreas

Tuesday, March 23, 2010 1:00 PM

Poster Session IV # 211, Tuesday Afternoon


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