MUC4-mediated regulation of acute phase protein lipocalin 2 through HER2/AKT/NF-κB signaling in pancreatic cancer.
OBJECTIVE
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-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 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-κB) and its clinical significance for prognosis of pancreatic cancer.
Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Statistics, Pathology, Surgery; Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska; and Division of Gastroenterology, Hepatology and Nutrition, UT Health-UT Health Science Center and Medical School at Houston, Houston, Texas.
Sukhwinder
S
Kaur
Neil
N
Sharma
Shiv Ram
SR
Krishn
Imay
I
Lakshmanan
Satyanarayana
S
Rachagani
Michael J
MJ
Baine
Lynette M
LM
Smith
Subodh M
SM
Lele
Aaron R
AR
Sasson
Sushovan
S
Guha
Kavita
K
Mallya
Judy M
JM
Anderson
Michael A
MA
Hollingsworth
Surinder K
SK
Batra
D000209:Acute-Phase Proteins / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D004797:Enzyme-Linked Immunosorbent Assay; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D055264:Mucin-4 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D000209:Acute-Phase Proteins; D014408:Biomarkers, Tumor; D000071068:Lipocalin-2; D054834:Lipocalins; D055264:Mucin-4; D016328:NF-kappa B; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C489506:LCN2 protein, human; C524658:MUC4 protein, human; C524659:Muc4 protein, mouse; C071332:Lcn2 protein, mouse