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Published in: Tumor Biology 6/2014

01-06-2014 | Research Article

CARMA3 is upregulated in human pancreatic carcinoma, and its depletion inhibits tumor proliferation, migration, and invasion

Authors: Shiyu Du, Liping Jia, Yanli Zhang, Long Fang, Xiang Zhang, Yanhua Fan

Published in: Tumor Biology | Issue 6/2014

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Abstract

Elevated CARMA3 expression has been reported to be involved in tumor progression of several cancer types. In the present study, we examined the expression pattern of CARMA3 protein and its biological roles in human pancreatic carcinoma. Using immunohistochemistry, we checked CARMA3 protein expression in 95 pancreatic ductal carcinoma specimens. We found that CARMA3 was overexpressed in 34 of 95 (35.8 %) specimens. A significant association was observed between CARMA3 overexpression with histological grade (p = 0.0099) and nodal status (p = 0.0126). To further explore its biological roles, we knocked down CARMA3 expression in CAPAN2 cell line using small interfering RNA (siRNA). MTT growth assay, wound healing assay, and Transwell assay showed that CARMA3 depletion inhibited cell proliferation, migration, and invasion. We also showed that CARMA3 depletion inhibited EGF-induced nuclear factor-kappaB (NF-κB) activation and its target genes’ expression. The effect of CARMA3 depletion on NF-κB signaling was significantly reduced in Bcl10-depleted cells. In conclusion, CARMA3 is overexpressed in pancreatic cancer and regulates malignant cell growth, invasion, and NF-κB signaling, which was dependent on its association with Bcl10.
Literature
2.
go back to reference Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.CrossRefPubMed Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.CrossRefPubMed
4.
go back to reference Wang BS, Liu Z, Sun SL, Zhao Y. Identification of genes and candidate agents associated with pancreatic cancer. Tumour Biol. 2014;35:81–8.CrossRefPubMed Wang BS, Liu Z, Sun SL, Zhao Y. Identification of genes and candidate agents associated with pancreatic cancer. Tumour Biol. 2014;35:81–8.CrossRefPubMed
5.
go back to reference Wang L, Gu F, Liu CY, Wang RJ, Li J, Xu JY. High level of FOXC1 expression is associated with poor prognosis in pancreatic ductal adenocarcinoma. Tumour Biol. 2013;34(2):853–8.CrossRefPubMed Wang L, Gu F, Liu CY, Wang RJ, Li J, Xu JY. High level of FOXC1 expression is associated with poor prognosis in pancreatic ductal adenocarcinoma. Tumour Biol. 2013;34(2):853–8.CrossRefPubMed
7.
go back to reference Wang L, Guo Y, Huang WJ, Ke X, Poyet JL, Manji GA, et al. Card10 is a novel caspase recruitment domain/membrane-associated guanylate kinase family member that interacts with BCL10 and activates NF-kappa B. J Biol Chem. 2001;276(24):21405–9.CrossRefPubMed Wang L, Guo Y, Huang WJ, Ke X, Poyet JL, Manji GA, et al. Card10 is a novel caspase recruitment domain/membrane-associated guanylate kinase family member that interacts with BCL10 and activates NF-kappa B. J Biol Chem. 2001;276(24):21405–9.CrossRefPubMed
8.
go back to reference Banan A, Zhang LJ, Farhadi A, Fields JZ, Shaikh M, Keshavarzian A. PKC-beta1 isoform activation is required for EGF-induced NF-kappaB inactivation and IkappaBalpha stabilization and protection of F-actin assembly and barrier function in enterocyte monolayers. Am J Physiol Cell Physiol. 2004;286(3):C723–38.CrossRefPubMed Banan A, Zhang LJ, Farhadi A, Fields JZ, Shaikh M, Keshavarzian A. PKC-beta1 isoform activation is required for EGF-induced NF-kappaB inactivation and IkappaBalpha stabilization and protection of F-actin assembly and barrier function in enterocyte monolayers. Am J Physiol Cell Physiol. 2004;286(3):C723–38.CrossRefPubMed
9.
go back to reference McAllister-Lucas LM, Ruland J, Siu K, Jin X, Gu S, Kim DS, et al. CARMA3/Bcl10/MALT1-dependent NF-kappaB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells. Proc Natl Acad Sci U S A. 2007;104(1):139–44.PubMedCentralCrossRefPubMed McAllister-Lucas LM, Ruland J, Siu K, Jin X, Gu S, Kim DS, et al. CARMA3/Bcl10/MALT1-dependent NF-kappaB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells. Proc Natl Acad Sci U S A. 2007;104(1):139–44.PubMedCentralCrossRefPubMed
10.
go back to reference Grabiner BC, Blonska M, Lin PC, You Y, Wang D, Sun J, et al. CARMA3 deficiency abrogates G protein-coupled receptor-induced NF-{kappa}B activation. Genes Dev. 2007;21(8):984–96.PubMedCentralCrossRefPubMed Grabiner BC, Blonska M, Lin PC, You Y, Wang D, Sun J, et al. CARMA3 deficiency abrogates G protein-coupled receptor-induced NF-{kappa}B activation. Genes Dev. 2007;21(8):984–96.PubMedCentralCrossRefPubMed
11.
go back to reference Wang D, You Y, Lin PC, Xue L, Morris SW, Zeng H, et al. Bcl10 plays a critical role in NF-kappaB activation induced by G protein-coupled receptors. Proc Natl Acad Sci U S A. 2007;104(1):145–50.PubMedCentralCrossRefPubMed Wang D, You Y, Lin PC, Xue L, Morris SW, Zeng H, et al. Bcl10 plays a critical role in NF-kappaB activation induced by G protein-coupled receptors. Proc Natl Acad Sci U S A. 2007;104(1):145–50.PubMedCentralCrossRefPubMed
12.
go back to reference Klemm S, Zimmermann S, Peschel C, Mak TW, Ruland J. Bcl10 and Malt1 control lysophosphatidic acid-induced NF-kappaB activation and cytokine production. Proc Natl Acad Sci U S A. 2007;104(1):134–8.PubMedCentralCrossRefPubMed Klemm S, Zimmermann S, Peschel C, Mak TW, Ruland J. Bcl10 and Malt1 control lysophosphatidic acid-induced NF-kappaB activation and cytokine production. Proc Natl Acad Sci U S A. 2007;104(1):134–8.PubMedCentralCrossRefPubMed
13.
go back to reference Wu GL, Yuan JL, Huang XD, Rong JF, Zhang LX, Liu YP, et al. Evaluating the expression of CARMA3 as a prognostic tumor marker in renal cell carcinoma. Tumour Biol. 2013;34:3431–5.CrossRefPubMed Wu GL, Yuan JL, Huang XD, Rong JF, Zhang LX, Liu YP, et al. Evaluating the expression of CARMA3 as a prognostic tumor marker in renal cell carcinoma. Tumour Biol. 2013;34:3431–5.CrossRefPubMed
14.
go back to reference Zhao T, Miao Z, Wang Z, Xu Y, Wu J, Liu X, et al. CARMA3 overexpression accelerates cell proliferation and inhibits paclitaxel-induced apoptosis through NF-kappaB regulation in breast cancer cells. Tumour Biol. 2013;34(5):3041–7.CrossRefPubMed Zhao T, Miao Z, Wang Z, Xu Y, Wu J, Liu X, et al. CARMA3 overexpression accelerates cell proliferation and inhibits paclitaxel-induced apoptosis through NF-kappaB regulation in breast cancer cells. Tumour Biol. 2013;34(5):3041–7.CrossRefPubMed
15.
go back to reference Miao Z, Zhao T, Wang Z, Xu Y, Song Y, Wu J, et al. CARMA3 is overexpressed in colon cancer and regulates NF-kappaB activity and cyclin D1 expression. Biochem Biophys Res Commun. 2012;425(4):781–7.CrossRefPubMed Miao Z, Zhao T, Wang Z, Xu Y, Song Y, Wu J, et al. CARMA3 is overexpressed in colon cancer and regulates NF-kappaB activity and cyclin D1 expression. Biochem Biophys Res Commun. 2012;425(4):781–7.CrossRefPubMed
16.
go back to reference Li Z, Qu L, Dong Q, Huang B, Li H, Tang Z, et al. Overexpression of CARMA3 in non-small-cell lung cancer is linked for tumor progression. PLoS One. 2012;7(5):e36903.PubMedCentralCrossRefPubMed Li Z, Qu L, Dong Q, Huang B, Li H, Tang Z, et al. Overexpression of CARMA3 in non-small-cell lung cancer is linked for tumor progression. PLoS One. 2012;7(5):e36903.PubMedCentralCrossRefPubMed
17.
go back to reference Maier HJ, Schmidt-Strassburger U, Huber MA, Wiedemann EM, Beug H, Wirth T. NF-kappaB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett. 2010;295(2):214–28.CrossRefPubMed Maier HJ, Schmidt-Strassburger U, Huber MA, Wiedemann EM, Beug H, Wirth T. NF-kappaB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett. 2010;295(2):214–28.CrossRefPubMed
18.
go back to reference Feng X, Miao G, Han Y, Xu Y. CARMA3 is overexpressed in human glioma and promotes cell invasion through MMP9 regulation in A172 cell line. Tumour Biol. 2014;35:149–54.CrossRefPubMed Feng X, Miao G, Han Y, Xu Y. CARMA3 is overexpressed in human glioma and promotes cell invasion through MMP9 regulation in A172 cell line. Tumour Biol. 2014;35:149–54.CrossRefPubMed
19.
go back to reference Li X, Liu D, Liu X, Jiang W, Zhou W, Yan W, et al. CpG ODN107 potentiates radiosensitivity of human glioma cells via TLR9-mediated NF-kappaB activation and NO production. Tumour Biol. 2012;33(5):1607–18.CrossRefPubMed Li X, Liu D, Liu X, Jiang W, Zhou W, Yan W, et al. CpG ODN107 potentiates radiosensitivity of human glioma cells via TLR9-mediated NF-kappaB activation and NO production. Tumour Biol. 2012;33(5):1607–18.CrossRefPubMed
20.
go back to reference Wang X, Deng Y, Mao Z, Ma X, Fan X, Cui L, et al. CCN1 promotes tumorigenicity through Rac1/Akt/NF-kappaB signaling pathway in pancreatic cancer. Tumour Biol. 2012;33(5):1745–58.CrossRefPubMed Wang X, Deng Y, Mao Z, Ma X, Fan X, Cui L, et al. CCN1 promotes tumorigenicity through Rac1/Akt/NF-kappaB signaling pathway in pancreatic cancer. Tumour Biol. 2012;33(5):1745–58.CrossRefPubMed
21.
go back to reference Jiang T, Grabiner B, Zhu Y, Jiang C, Li H, You Y, et al. CARMA3 is crucial for EGFR-induced activation of NF-kappaB and tumor progression. Cancer Res. 2011;71(6):2183–92.PubMedCentralCrossRefPubMed Jiang T, Grabiner B, Zhu Y, Jiang C, Li H, You Y, et al. CARMA3 is crucial for EGFR-induced activation of NF-kappaB and tumor progression. Cancer Res. 2011;71(6):2183–92.PubMedCentralCrossRefPubMed
22.
go back to reference Wasif N, Ko CY, Farrell J, Wainberg Z, Hines OJ, Reber H, et al. Impact of tumor grade on prognosis in pancreatic cancer: should we include grade in AJCC staging? Ann Surg Oncol. 2010;17(9):2312–20.PubMedCentralCrossRefPubMed Wasif N, Ko CY, Farrell J, Wainberg Z, Hines OJ, Reber H, et al. Impact of tumor grade on prognosis in pancreatic cancer: should we include grade in AJCC staging? Ann Surg Oncol. 2010;17(9):2312–20.PubMedCentralCrossRefPubMed
23.
go back to reference Mahanivong C, Chen HM, Yee SW, Pan ZK, Dong Z, Huang S. Protein kinase C alpha-CARMA3 signaling axis links Ras to NF-kappa B for lysophosphatidic acid-induced urokinase plasminogen activator expression in ovarian cancer cells. Oncogene. 2008;27(9):1273–80.PubMedCentralCrossRefPubMed Mahanivong C, Chen HM, Yee SW, Pan ZK, Dong Z, Huang S. Protein kinase C alpha-CARMA3 signaling axis links Ras to NF-kappa B for lysophosphatidic acid-induced urokinase plasminogen activator expression in ovarian cancer cells. Oncogene. 2008;27(9):1273–80.PubMedCentralCrossRefPubMed
24.
go back to reference Tashiro E, Tsuchiya A, Imoto M. Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression. Cancer Sci. 2007;98(5):629–35.CrossRefPubMed Tashiro E, Tsuchiya A, Imoto M. Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression. Cancer Sci. 2007;98(5):629–35.CrossRefPubMed
25.
go back to reference Witzel II, Koh LF, Perkins ND. Regulation of cyclin D1 gene expression. Biochem Soc Trans. 2010;38(Pt 1):217–22.CrossRefPubMed Witzel II, Koh LF, Perkins ND. Regulation of cyclin D1 gene expression. Biochem Soc Trans. 2010;38(Pt 1):217–22.CrossRefPubMed
26.
go back to reference Liu CY, Xu JY, Shi XY, Huang W, Ruan TY, Xie P, et al. M2-polarized tumor-associated macrophages promoted epithelial-mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway. Lab Invest. 2013;93(7):844–54.CrossRefPubMed Liu CY, Xu JY, Shi XY, Huang W, Ruan TY, Xie P, et al. M2-polarized tumor-associated macrophages promoted epithelial-mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway. Lab Invest. 2013;93(7):844–54.CrossRefPubMed
Metadata
Title
CARMA3 is upregulated in human pancreatic carcinoma, and its depletion inhibits tumor proliferation, migration, and invasion
Authors
Shiyu Du
Liping Jia
Yanli Zhang
Long Fang
Xiang Zhang
Yanhua Fan
Publication date
01-06-2014
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 6/2014
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-014-1791-6

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