Loss of RKIP Expression in Colorectal Cancer Is Associated with Activation of the NF-κB Signaling Pathway and Epithelial-Mesenchymal Transition
Viktor H Koelzer, Heather Dawson, Eva Karamitopoulou, Alessandro Lugli, Inti Zlobec. University of Bern, Bern, Switzerland
Background: Nuclear factor κB (NF-κB) signaling provides a fertile soil to invading cancer cells through regulation of stroma-associated genes and epithelial-mesenchymal transition (EMT). Raf-1 Kinase Inhibitor Protein (RKIP) counteracts NF-κB activation and impairs invasiveness and the ability to form metastases in cancer cells. The aim of this study was the combined geographic analysis of RKIP and NF-κB expression for the prediction of clinico-pathological features and outcome in colorectal cancer.
Design: RKIP expression was assessed in 221 CRCs with full clinico-pathological information by immunohistochemistry in 10HPF of normal mucosa, tumor center, invasion front and tumor buds using whole tissue sections; Nuclear NF-κB expression in tumor cells was assessed using a multi-punch tissue microarray representing each histologic zone. The geographic expression pattern of RKIP was assessed for correlation with survival, clinico-pathological characteristics and features of EMT including tumor budding, infiltrative tumor border configuration and NF-κB activation.
Results: RKIP was diffusely expressed in normal mucosa and progressively lost towards tumor center and front (27%, 14% and 8% RKIP-positivity, respectively; p<0.0001). Only 0.4% of tumor buds were RKIP-positive. In the tumor center, loss of RKIP expression predicted metastatic disease (p=0.0307), vascular invasion (p=0.0506), frequent tumor budding (p=0.0112) and an invasive border configuration (p=0.0084). Further, loss of RKIP correlated strongly with NF-κB activation (p=0.0129). RKIP loss was more common in mismatch repair-deficient cancers (p=0.0191). Interestingly, KRAS mutation did not show an impact on RKIP expression. Loss of RKIP expression in the tumor center was an independent prognostic indicator for survival (HR (95%CI): 0.47 (0.28-0.79) p=0.0042) and predicted reduced response to adjuvant chemotherapy.
Conclusions: The clinical relevance of RKIP expression as an independent prognostic factor is restricted to the tumor center. Loss of RKIP in this geographic area strongly predicts features of EMT including an increased activation of the NF-κB signaling pathway and correlates with frequent distant metastasis.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 102, Monday Morning