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 language | English (US) |
|---|---|
| Pages (from-to) | 688-700 |
| Number of pages | 13 |
| Journal | Clinical Cancer Research |
| Volume | 20 |
| Issue number | 3 |
| DOIs | |
| State | Published - Feb 11 2014 |
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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 journal › Article
}
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.
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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
C2 - 24240113
AN - SCOPUS:84893443202
VL - 20
SP - 688
EP - 700
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 3
ER -