MUC4-Mediated Regulation of Acute Phase Protein Lipocalin 2 through HER2/AKT/NF-κB Signaling in Pancreatic Cancer

Purpose: MUC4 shows aberrant expression in early pancreatic lesions and a high specificity for pancreatic cancer. It thus has a high potential to be a sensitive and specific biomarker. Unfortunately, its low serum level limits its diagnostic/prognostic potential. We here report that a multifaceted 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 that MUC4 regulates lipocalin 2 by stabilizing HER2 and stimulating AKT, which results in the activation of NF-kappa B. 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 = 0.002) from rapid autopsy tissue sample from patients with pancreatic cancer as well as in serum and tissue samples from spontaneous KRASG(12)D mouse pancreatic cancer model (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, P = 0.014). Analyses of pre- and postchemotherapy patients showed higher lipocalin 2 levels in prechemotherapy patients [ 121.7 ng/mL; 95% confidence interval (CI), 98.1-150.9] in comparison with the postchemotherapy (92.6 ng/mL; 95% CI, 76.7-111.6; P = 0.06) group. Conclusions: This study delineates the association and the downstream mechanisms of MUC4-regulated elevation of lipocalin-2 (via HER2/AKT/NF-kappa B) and its clinical significance for prognosis of pancreatic cancer. (C) 2013 AACR.