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

Sukwinder 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 Kumar Batra

Research output: Contribution to journalArticle

18 Citations (Scopus)

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

Acute-Phase Proteins
Pancreatic Neoplasms
Confidence Intervals
Lipocalin-2
Luciferases
Serum
Autopsy
Research Design
Biomarkers

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

MUC4-mediated regulation of acute phase protein lipocalin 2 through HER2/AKT/NF-κB signaling in pancreatic cancer. / Kaur, Sukwinder; Sharma, Neil; Krishn, Shiv Ram; Lakshmanan, Imay; Rachagani, Satyanarayana; Baine, Michael J.; Smith, Lynette M; Lele, Subodh M; Sasson, Aaron R.; Guha, Sushovan; Mallya, Kavita; Anderson, Judy M.; Hollingsworth, Michael A; Batra, Surinder Kumar.

In: Clinical Cancer Research, Vol. 20, No. 3, 11.02.2014, p. 688-700.

Research output: Contribution to journalArticle

Kaur, Sukwinder ; Sharma, Neil ; Krishn, Shiv Ram ; Lakshmanan, Imay ; Rachagani, Satyanarayana ; Baine, Michael J. ; Smith, Lynette M ; Lele, Subodh M ; Sasson, Aaron R. ; Guha, Sushovan ; Mallya, Kavita ; Anderson, Judy M. ; Hollingsworth, Michael A ; Batra, Surinder Kumar. / MUC4-mediated regulation of acute phase protein lipocalin 2 through HER2/AKT/NF-κB signaling in pancreatic cancer. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 3. pp. 688-700.
@article{dec7513b3f9449da95aff8a4e68d9b5e,
title = "MUC4-mediated regulation of acute phase protein lipocalin 2 through HER2/AKT/NF-κB signaling in pancreatic cancer",
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.",
author = "Sukwinder Kaur and Neil Sharma and Krishn, {Shiv Ram} and Imay Lakshmanan and Satyanarayana Rachagani and Baine, {Michael J.} and Smith, {Lynette M} and Lele, {Subodh M} and Sasson, {Aaron R.} and Sushovan Guha and Kavita Mallya and Anderson, {Judy M.} and Hollingsworth, {Michael A} and Batra, {Surinder Kumar}",
year = "2014",
month = "2",
day = "11",
doi = "10.1158/1078-0432.CCR-13-2174",
language = "English (US)",
volume = "20",
pages = "688--700",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "3",

}

TY - JOUR

T1 - MUC4-mediated regulation of acute phase protein lipocalin 2 through HER2/AKT/NF-κB signaling in pancreatic cancer

AU - Kaur, Sukwinder

AU - Sharma, Neil

AU - Krishn, Shiv Ram

AU - Lakshmanan, Imay

AU - Rachagani, Satyanarayana

AU - Baine, Michael J.

AU - Smith, Lynette M

AU - Lele, Subodh M

AU - Sasson, Aaron R.

AU - Guha, Sushovan

AU - Mallya, Kavita

AU - Anderson, Judy M.

AU - Hollingsworth, Michael A

AU - Batra, Surinder Kumar

PY - 2014/2/11

Y1 - 2014/2/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84893443202&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84893443202&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-13-2174

DO - 10.1158/1078-0432.CCR-13-2174

M3 - Article

VL - 20

SP - 688

EP - 700

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 3

ER -