MUC4-MediatedRegulation of Acute PhaseProtein Lipocalin 2 through HER2/AKT/NF-kB Signaling in Pancreatic Cancer

Purpose:MUC4 shows aberrant expression in early pancreatic lesions and ahigh specificity for pancreatic cancer. It thus has ahighpotential tobe a sensitive and specific biomarker.Unfortunately, its low serum level limits its diagnostic/prognostic potential.We here report that amultifaceted acute phase protein lipocalin 2, regulated by MUC4, could be a potential diagnostic/prognostic marker for pancreatic cancer. Experimental Designs and Results: Overexpression/knockdown, luciferase reporter and molecular inhibition studies revealed thatMUC4 regulates lipocalin 2 by stabilizingHER2 and stimulating AKT,which results in the activation of NF-kB. Immunohistochemical analyses of lipocalin 2 and MUC4 showed a significant positive correlation between MUC4 and lipocalin 2 in primary, metastatic tissues (Spearman correlation coefficient 0.71, P 1⁄4 0.002) from rapid autopsy tissue sample from patients with pancreatic cancer as well as in serum and tissue samples from spontaneous KRASGDmouse pancreatic cancermodel (Spearman correlation coefficient 0.98, P < 0.05). Lipocalin 2 levels increased progressively with disease advancement (344.2 22.8 ng/mL for 10 weeks to 3067.2 572.6 for 50 weeks; P < 0.0001). In human pancreatic cancer cases, significantly elevated levels of lipocalin 2 were observed in patients with pancreatic cancer (148 13.18 ng/mL) in comparison with controls (73.27 4.9 ng/mL, P1⁄4 0.014). Analyses of preandpostchemotherapy patients showed higher lipocalin 2 levels in prechemotherapy patients [121.7 ng/mL; 95% confidence interval (CI), 98.1–150.9] in comparisonwith the postchemotherapy (92.6 ng/mL; 95%CI, 76.7–111.6; P 1⁄4 0.06) group. Conclusions: This study delineates the association and the downstreammechanisms ofMUC4-regulated elevation of lipocalin-2 (via HER2/AKT/NF-kB) and its clinical significance for prognosis of pancreatic cancer. Clin Cancer Res; 20(3); 1–13. 2013 AACR.