MUC4-mediated regulation of acute phase protein lipocalin 2 through HER2/AKT/NF-κB signaling in pancreatic cancer

Sukhwinder Kaur, Neil Sharma, Shiv Ram Krishn, Imay Lakshmanan, Satyanarayana Rachagani, Michael J. Baine, Lynette M. Smith, Subodh M. Lele, Aaron R. Sasson, Sushovan Guha, Kavita Mallya, Judy M. Anderson, Michael A. Hollingsworth, Surinder K. Batra

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Purpose:MUC4shows 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. Wehere 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 thatMUC4regulates lipocalin 2 by stabilizing HER2 and stimulating AKT, which results in the activation of NF-κB. 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 KRASG12Dmouse 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 preand 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-κB) and its clinical significance for prognosis of pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)688-700
Number of pages13
JournalClinical Cancer Research
Volume20
Issue number3
DOIs
StatePublished - Feb 11 2014

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this