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Published in: Surgery Today 2/2013

01-02-2013 | Original Article

Nuclear factor κB activity correlates with the progression and prognosis of pancreatic cancer in a mouse model

Authors: Kenei Furukawa, Tadashi Uwagawa, Koichiro Haruki, Yuki Fujiwara, Tomonori Iida, Hiroaki Shiba, Takeyuki Misawa, Toya Ohashi, Katsuhiko Yanaga

Published in: Surgery Today | Issue 2/2013

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Abstract

Introduction

Constitutive NF-κB activation is considered to play a key role in the aggressive behavior of pancreatic cancer. Although NF-κB in tumors may contribute to aggressive characteristic features via transcription of angiogenesis and invasion-related factors, there is no definitive evidence showing a correlation between quantitated NF-κB activity and prognosis. In this study, we quantitated NF-κB activity of various human pancreatic cancer cell lines and evaluated whether NF-κB activity was related to tumor progression and prognosis for pancreatic cancer in mice.

Materials and methods

We quantitated NF-κB activity in six pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-2, MIAPaCa-2, Panc-1 and PL45) and evaluated downstream target genes of NF-κB such as VEGF, IL-8 and MMP-9 in vitro. Next, we evaluated tumor progression and prognosis using subcutaneous tumor model in vivo between cell lines with the highest and lowest NF-κB activity.

Results

BxPC-3 had the highest and AsPC-1 had the lowest NF-κB activity in the 6 cell lines. Expression of VEGF, IL-8 and MMP-9 in BxPC-3 was significantly higher than those in AsPC-1 cells in vitro (p < 0.001) and tumor growth in BxPC-3 was faster than that in AsPC-1 group (p < 0.001) resulting in worse survival in vivo (p = 0.0339).

Conclusion

These results suggested that NF-κB activity is related to expression of its downstream target genes, tumor progression and prognosis in experimental pancreatic cancer model.
Literature
1.
go back to reference Niederhuber JE, Brennan MF, Menck HR. The National CancerDate Base report on pancreatic cancer. Cancer. 1995;76:1671–7.PubMedCrossRef Niederhuber JE, Brennan MF, Menck HR. The National CancerDate Base report on pancreatic cancer. Cancer. 1995;76:1671–7.PubMedCrossRef
2.
go back to reference Sohn TA, Yeo CJ, Cameron JL, Koniaris L, Kaushal S, Abrams RA, et al. Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg. 2000;4:567–79.PubMedCrossRef Sohn TA, Yeo CJ, Cameron JL, Koniaris L, Kaushal S, Abrams RA, et al. Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg. 2000;4:567–79.PubMedCrossRef
3.
go back to reference Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403–13.PubMed Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403–13.PubMed
4.
go back to reference Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, Benson AB 3rd. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol. 2002;20:3270–5.PubMedCrossRef Berlin JD, Catalano P, Thomas JP, Kugler JW, Haller DG, Benson AB 3rd. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol. 2002;20:3270–5.PubMedCrossRef
5.
go back to reference Chen F, Castranova V, Shi X. New insights into the role of nuclear factor-κB in cell growth regulation. Am J Pathol. 2001;159:387–97.PubMedCrossRef Chen F, Castranova V, Shi X. New insights into the role of nuclear factor-κB in cell growth regulation. Am J Pathol. 2001;159:387–97.PubMedCrossRef
6.
go back to reference Amer BA, David B. An essential role for NF-κB in preventing TNF-alpha-induced cell death. Science. 1996;274:782–4.CrossRef Amer BA, David B. An essential role for NF-κB in preventing TNF-alpha-induced cell death. Science. 1996;274:782–4.CrossRef
7.
go back to reference Antwerp VDJ, Seamus MJ, Tal K, Douglas GR, Inder VM. Suppression of TNF-alpha-induced apoptosis by NF-κB. Science. 1996;274:787–9.PubMedCrossRef Antwerp VDJ, Seamus MJ, Tal K, Douglas GR, Inder VM. Suppression of TNF-alpha-induced apoptosis by NF-κB. Science. 1996;274:787–9.PubMedCrossRef
8.
go back to reference Karin M, Lin A. NF-κB at the crossroads of life and death. Nature Immunol. 2002;3:221–7.CrossRef Karin M, Lin A. NF-κB at the crossroads of life and death. Nature Immunol. 2002;3:221–7.CrossRef
9.
go back to reference Huang S, Robinson JB, DeGuzman A, Bucana CD, Fiddler IJ. Blockade of nuclear factor-κB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res. 2000;60:5334–9.PubMed Huang S, Robinson JB, DeGuzman A, Bucana CD, Fiddler IJ. Blockade of nuclear factor-κB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res. 2000;60:5334–9.PubMed
10.
go back to reference Matsumoto G, Namekawa J, Muta M, Nakamura T, Bando H, Tohyama K, et al. Targeting of nuclear factor κB pathways by dehydroxymethyleoxyquinomicin, a novel inhibitor of breast carcinomas: antitumor and antiangiogenic potential in vivo. Clin Cancer Res. 2005;11:1287–93.PubMed Matsumoto G, Namekawa J, Muta M, Nakamura T, Bando H, Tohyama K, et al. Targeting of nuclear factor κB pathways by dehydroxymethyleoxyquinomicin, a novel inhibitor of breast carcinomas: antitumor and antiangiogenic potential in vivo. Clin Cancer Res. 2005;11:1287–93.PubMed
11.
go back to reference Kikuchi E, Horiguchi Y, Nakashima J, Kuroda K, Oya M, Ohigashi T, et al. Suppression of hormone-refractory prostate cancer by a novel nuclear factor κB inhibitor in nude mice. Cancer Res. 2003;63:107–10.PubMed Kikuchi E, Horiguchi Y, Nakashima J, Kuroda K, Oya M, Ohigashi T, et al. Suppression of hormone-refractory prostate cancer by a novel nuclear factor κB inhibitor in nude mice. Cancer Res. 2003;63:107–10.PubMed
12.
go back to reference Huang S, Pettaway CA, Uehara H, Bucana CD, Fidler IJ. Blockade of NF-κB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene. 2001;20:4188–97.PubMedCrossRef Huang S, Pettaway CA, Uehara H, Bucana CD, Fidler IJ. Blockade of NF-κB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene. 2001;20:4188–97.PubMedCrossRef
13.
go back to reference Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiano PJ. The nuclear factor-κB RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res. 1999;5:119–27.PubMed Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiano PJ. The nuclear factor-κB RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res. 1999;5:119–27.PubMed
14.
go back to reference Wang W, Abbruzzese JL, Evans DB, Chiano PJ. Overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated by constitutively activated RelA. Oncogene. 1999;18:4554–63.PubMedCrossRef Wang W, Abbruzzese JL, Evans DB, Chiano PJ. Overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated by constitutively activated RelA. Oncogene. 1999;18:4554–63.PubMedCrossRef
15.
go back to reference Fujioka S, Sclabas GM, Schmidit C, Niu J, Frederick WA, Dong QG, et al. Inhibition of constitutive NF-κB activity by IκBαM suppresses tumorigenesis. Oncogene. 2003;22:1365–70.PubMedCrossRef Fujioka S, Sclabas GM, Schmidit C, Niu J, Frederick WA, Dong QG, et al. Inhibition of constitutive NF-κB activity by IκBαM suppresses tumorigenesis. Oncogene. 2003;22:1365–70.PubMedCrossRef
16.
go back to reference Fujioka S, Sclabas GM, Schmidit C, Frederick WA, Dong QG, Abbruzzese JL, et al. Function of nuclear κB in pancreatic cancer metastasis. Clin Cancer Res. 2003;9:346–54.PubMed Fujioka S, Sclabas GM, Schmidit C, Frederick WA, Dong QG, Abbruzzese JL, et al. Function of nuclear κB in pancreatic cancer metastasis. Clin Cancer Res. 2003;9:346–54.PubMed
17.
go back to reference Uwagawa T, Li Z, Zhe C, Xia Q, Peng B, Sclabas GM, et al. Mechanisms of synthetic serine protease inhibitor (FUT-175)-mediated cell death. Cancer. 2007;109:2142–53.PubMedCrossRef Uwagawa T, Li Z, Zhe C, Xia Q, Peng B, Sclabas GM, et al. Mechanisms of synthetic serine protease inhibitor (FUT-175)-mediated cell death. Cancer. 2007;109:2142–53.PubMedCrossRef
18.
go back to reference Furukawa K, Iida T, Shiba H, Fujiwara Y, Uwagawa T, Shimada Y, et al. Anti-tumor effect by inhibition of NF-κB activation using nafamostat mesylate for pancreatic cancer in a mouse model. Oncol Rep. 2010;24:843–50.PubMedCrossRef Furukawa K, Iida T, Shiba H, Fujiwara Y, Uwagawa T, Shimada Y, et al. Anti-tumor effect by inhibition of NF-κB activation using nafamostat mesylate for pancreatic cancer in a mouse model. Oncol Rep. 2010;24:843–50.PubMedCrossRef
19.
go back to reference Uwagawa T, Misawa T, Sakamoto T, Ito R, Gocho T, Shiba H, et al. A phase I study of full-dose gemcitabine and regional arterial infusion of nafamostat mesylate for advanced pancreatic cancer. Ann Oncol. 2009;20:239–43.PubMedCrossRef Uwagawa T, Misawa T, Sakamoto T, Ito R, Gocho T, Shiba H, et al. A phase I study of full-dose gemcitabine and regional arterial infusion of nafamostat mesylate for advanced pancreatic cancer. Ann Oncol. 2009;20:239–43.PubMedCrossRef
20.
go back to reference Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res. 2008;14:4491–9.PubMedCrossRef Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res. 2008;14:4491–9.PubMedCrossRef
21.
go back to reference Shimada Y, Fukuda T, Aoki K, Yukawa T, Iwamuro S, Ohkawa K, et al. A protocol for immunoaffinity separation of the accumulated ubiquitin-protein conjugates solubilized with sodium dodecyl sulfate. Anal Biochem. 2008;377:77–82.PubMedCrossRef Shimada Y, Fukuda T, Aoki K, Yukawa T, Iwamuro S, Ohkawa K, et al. A protocol for immunoaffinity separation of the accumulated ubiquitin-protein conjugates solubilized with sodium dodecyl sulfate. Anal Biochem. 2008;377:77–82.PubMedCrossRef
22.
go back to reference Arlt A, Gehrz A, Müerköster S, Vorndamm J, Kruse ML, Fölsch UR, et al. Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene. 2003;22:3243–51.PubMedCrossRef Arlt A, Gehrz A, Müerköster S, Vorndamm J, Kruse ML, Fölsch UR, et al. Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene. 2003;22:3243–51.PubMedCrossRef
23.
go back to reference Arlt A, Vorndamm J, Breitenbroich M, Fölsch UR, Kalthoff H, Schmidt WE, et al. Inhibition of NF-kappaB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin. Oncogene. 2001;20:859–68.PubMedCrossRef Arlt A, Vorndamm J, Breitenbroich M, Fölsch UR, Kalthoff H, Schmidt WE, et al. Inhibition of NF-kappaB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin. Oncogene. 2001;20:859–68.PubMedCrossRef
24.
go back to reference Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS Jr. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science. 1998;281:1680–3.PubMedCrossRef Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS Jr. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science. 1998;281:1680–3.PubMedCrossRef
25.
go back to reference Weichert W, Boehm M, Gekeler V, Bahra M, Langrehr J, Neuhaus P, et al. High expression of RelA/p65 is associated with activation of nuclear factor-kappaB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis. Br J Cancer. 2007;97:523–30.PubMedCrossRef Weichert W, Boehm M, Gekeler V, Bahra M, Langrehr J, Neuhaus P, et al. High expression of RelA/p65 is associated with activation of nuclear factor-kappaB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis. Br J Cancer. 2007;97:523–30.PubMedCrossRef
26.
go back to reference Le X, Shi Q, Wang B, Xiong Q, Qian C, Peng Z, et al. Molecular regulation of constitutive expression of interleukin-8 in human pancreatic adenocarcinoma. J Interferon Cytokine Res. 2000;20:935–46.PubMedCrossRef Le X, Shi Q, Wang B, Xiong Q, Qian C, Peng Z, et al. Molecular regulation of constitutive expression of interleukin-8 in human pancreatic adenocarcinoma. J Interferon Cytokine Res. 2000;20:935–46.PubMedCrossRef
27.
go back to reference Shi Q, Abbruzzese JL, Huang S, Fidler IJ, Xiong Q, Xie K. Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin Cancer Res. 1999;5:3711–21.PubMed Shi Q, Abbruzzese JL, Huang S, Fidler IJ, Xiong Q, Xie K. Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin Cancer Res. 1999;5:3711–21.PubMed
28.
go back to reference Nakagawa Y, Aoki T, Kasuya K, Tsuchida A, Koyanagi Y. Histologic features of venous invasion, expression of vascular endothelial growth factor and matrix metalloproteinase-2 and matrix metalloproteinase-9, and the relation with liver metastasis in pancreatic cancer. Pancreas. 2002;24:169–78.CrossRef Nakagawa Y, Aoki T, Kasuya K, Tsuchida A, Koyanagi Y. Histologic features of venous invasion, expression of vascular endothelial growth factor and matrix metalloproteinase-2 and matrix metalloproteinase-9, and the relation with liver metastasis in pancreatic cancer. Pancreas. 2002;24:169–78.CrossRef
29.
go back to reference Aggarwal BB, Shishodia S, Takada Y, Banerjee S, Newman RA, Bueso-Ramos CE, et al. Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. Clin Cancer Res. 2005;11:7490–8.PubMedCrossRef Aggarwal BB, Shishodia S, Takada Y, Banerjee S, Newman RA, Bueso-Ramos CE, et al. Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. Clin Cancer Res. 2005;11:7490–8.PubMedCrossRef
30.
go back to reference Fujiwara Y, Furukawa K, Haruki K, Shimada Y, Iida T, Shiba H, et al. Nafamostat mesylate can prevent adhesion, invasion and peritoneal dissemination of pancreatic cancer thorough nuclear factor-kappa B inhibition. J Hepatobiliary Pancreat Sci. 2011;18:731–9.PubMedCrossRef Fujiwara Y, Furukawa K, Haruki K, Shimada Y, Iida T, Shiba H, et al. Nafamostat mesylate can prevent adhesion, invasion and peritoneal dissemination of pancreatic cancer thorough nuclear factor-kappa B inhibition. J Hepatobiliary Pancreat Sci. 2011;18:731–9.PubMedCrossRef
31.
go back to reference Lim JE, Chien MW, Earle CCP. Prognostic factors following curative resection for pancreatic adenocarcinoma: a population-based, linked database analysis of 396 patients. Ann Surg. 2003;237:74–85.PubMedCrossRef Lim JE, Chien MW, Earle CCP. Prognostic factors following curative resection for pancreatic adenocarcinoma: a population-based, linked database analysis of 396 patients. Ann Surg. 2003;237:74–85.PubMedCrossRef
32.
go back to reference Nakamori S, Yashima K, Murakami Y, Ishikawa O, Ohigashi H, Imaoka S, et al. Association of p53 gene mutations with short survival in pancreatic adenocarcinoma. Jpn J Cancer Res. 1995;86:174–81.PubMedCrossRef Nakamori S, Yashima K, Murakami Y, Ishikawa O, Ohigashi H, Imaoka S, et al. Association of p53 gene mutations with short survival in pancreatic adenocarcinoma. Jpn J Cancer Res. 1995;86:174–81.PubMedCrossRef
33.
go back to reference Yamamoto S, Tomita Y, Hoshida Y, Morooka T, Nagano H, Dono K, et al. Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma. Clin Cancer Res. 2004;10:2846–50.PubMedCrossRef Yamamoto S, Tomita Y, Hoshida Y, Morooka T, Nagano H, Dono K, et al. Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma. Clin Cancer Res. 2004;10:2846–50.PubMedCrossRef
34.
go back to reference Sipos B, Möser S, Kalthoff H, Török V, Löhr M, Klöppel G. A comprehensive characterization of pancreatic ductal carcinoma cell lines: towards the establishment of an in vitro research platform. Virchows Arch. 2003;442:444–52.PubMed Sipos B, Möser S, Kalthoff H, Török V, Löhr M, Klöppel G. A comprehensive characterization of pancreatic ductal carcinoma cell lines: towards the establishment of an in vitro research platform. Virchows Arch. 2003;442:444–52.PubMed
Metadata
Title
Nuclear factor κB activity correlates with the progression and prognosis of pancreatic cancer in a mouse model
Authors
Kenei Furukawa
Tadashi Uwagawa
Koichiro Haruki
Yuki Fujiwara
Tomonori Iida
Hiroaki Shiba
Takeyuki Misawa
Toya Ohashi
Katsuhiko Yanaga
Publication date
01-02-2013
Publisher
Springer Japan
Published in
Surgery Today / Issue 2/2013
Print ISSN: 0941-1291
Electronic ISSN: 1436-2813
DOI
https://doi.org/10.1007/s00595-012-0279-5

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