Diagnostic Pathology | |
MMP2 and MMP7 at the invasive front of gastric cancer are not associated with mTOR expression | |
Peter Malfertheiner2  Michael Vieth1  Elizabeth Bird-Lieberman3  Frank Meyer5  Doerthe Jechorek1  Michael Selgrad2  Thomas Wex4  Alexander Link2  Cosima Langner2  Tina Seidel2  Jan Bornschein2  | |
[1] Institute for Pathology, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg 39120, Germany;Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg 39120, Germany;Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Medicine, University of Oxford, Oxford, UK;Department of Molecular Genetics, Medical Laboratory for Clinical Chemistry, Microbiology and Infectious Diseases, Am Neustädter Feld 47, Magdeburg 39124, Germany;Department for General, Visceral and Vascular Surgery, Otto-von-Guericke University, Leipziger Str. 44, Magdeburg 39120, Germany | |
关键词: MMP9; MMP7; MMP2; mTOR; Gastric cancer; | |
Others : 1235139 DOI : 10.1186/s13000-015-0449-z |
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received in 2015-03-09, accepted in 2015-12-05, 发布年份 2015 | |
【 摘 要 】
Background
Regulation of MMP expression by activation of mTOR signalling has been demonstrated for several tumor types, but has thus far not been confirmed in gastric cancer.
Findings
The study compromised 128 patients who underwent gastric resection for cancer (66.4 % male; 86 intestinal, 42 diffuse type). Immunohistochemical staining of MMPs was performed to analyse the topographical pattern of MMP expression at the tumor center and the invasive front, respectively. MMP2 showed higher expression at the invasive front compared to the tumor center, whereas MMP7 staining scores were higher in the tumor center, and there was no difference for MMP9. The expression of p-mTOR was higher in the tumor center than at the invasive front, with a similar trend for mTOR. For intestinal type gastric cancer there was a weak correlation of MMP9 with expression of mTOR in the tumor center. Otherwise, there was no correlation of the MMPs with mTOR. By treatment of MKN45 gastric cancer cells with rapamycin, a reduction of p-mTOR in the Western blot was achieved; however, expression of MMPs remained unaffected.
Conclusions
Expression of MMP2 and MMP7 in gastric cancer is not associated with mTOR, MMP9 expression might be related to mTOR signalling in a subset of tumors.
【 授权许可】
2015 Bornschein et al.
【 预 览 】
Files | Size | Format | View |
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20160102031523783.pdf | 1906KB | download | |
Fig. 1. | 303KB | Image | download |
【 图 表 】
Fig. 1.
【 参考文献 】
- [1]Kubben FJ, Sier CF, van Duijn W, Griffioen G, Hanemaaijer R, van de Velde CJ et al.. Matrix metalloproteinase-2 is a consistent prognostic factor in gastric cancer. Br J Cancer. 2006; 94(7):1035-1040.
- [2]Nomura H, Fujimoto N, Seiki M, Mai M, Okada Y. Enhanced production of matrix metalloproteinases and activation of matrix metalloproteinase 2 (gelatinase A) in human gastric carcinomas. Int J Cancer. 1996; 69(1):9-16.
- [3]Zhang M, Zhu GY, Gao HY, Zhao SP, Xue Y. Expression of tissue levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in gastric adenocarcinoma. J Surg Oncol. 2010; 103(3):243-247.
- [4]Zhang D, Bar-Eli M, Meloche S, Brodt P. Dual regulation of MMP-2 expression by the type 1 insulin-like growth factor receptor: the phosphatidylinositol 3-kinase/Akt and Raf/ERK pathways transmit opposing signals. J Biol Chem. 2004; 279(19):19683-19690.
- [5]Adachi Y, Li R, Yamamoto H, Min Y, Piao W, Wang Y et al.. Insulin-like growth factor-I receptor blockade reduces the invasiveness of gastrointestinal cancers via blocking production of matrilysin. Carcinogenesis. 2009; 30(8):1305-1313.
- [6]Populo H, Lopes JM, Soares P. The mTOR Signalling Pathway in Human Cancer. Int J Mol Sci. 2012; 13(2):1886-1918.
- [7]Yu G, Wang J, Chen Y, Wang X, Pan J, Li G et al.. Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of chinese patients with gastric cancer. Clin Cancer Res. 2009; 15(5):1821-1829.
- [8]Murayama T, Inokuchi M, Takagi Y, Yamada H, Kojima K, Kumagai J et al.. Relation between outcomes and localisation of p-mTOR expression in gastric cancer. Br J Cancer. 2009; 100(5):782-788.
- [9]Xu DZ, Geng QR, Tian Y, Cai MY, Fang XJ, Zhan YQ et al.. Activated mammalian target of rapamycin is a potential therapeutic target in gastric cancer. BMC Cancer. 2010; 10:536. BioMed Central Full Text
- [10]Zhou HY, Wong AS. Activation of p70S6K induces expression of matrix metalloproteinase 9 associated with hepatocyte growth factor-mediated invasion in human ovarian cancer cells. Endocrinology. 2006; 147(5):2557-2566.
- [11]Ko HS, Lee HJ, Kim SH, Lee EO. Piceatannol suppresses breast cancer cell invasion through the inhibition of MMP-9: involvement of PI3K/AKT and NF-kappaB pathways. J Agric Food Chem. 2012; 60(16):4083-4089.
- [12]Ji Y, Yang X, Li J, Lu Z, Li X, Yu J et al.. IL-22 promotes the migration and invasion of gastric cancer cells via IL-22R1/AKT/MMP-9 signaling. Int J Clin Exp Pathol. 2014; 7(7):3694-3703.
- [13]Remmele W, Stegner HE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 1987; 8(3):138-140.
- [14]Zhao F, Zhang Q, Kang C, Cui X, Wang T, Xu P et al.. Suppression of matrix metalloproteinase-9 expression by RNA interference inhibits SGC7901 gastric adenocarcinoma cell growth and invasion in vitro and in vivo. Med Oncol. 2010; 27(3):774-784.
- [15]David L, Nesland JM, Holm R, Sobrinho-Simoes M. Expression of laminin, collagen IV, fibronectin, and type IV collagenase in gastric carcinoma. An immunohistochemical study of 87 patients. Cancer. 1994; 73(3):518-527.
- [16]McCaig C, Duval C, Hemers E, Steele I, Pritchard DM, Przemeck S et al.. The role of matrix metalloproteinase-7 in redefining the gastric microenvironment in response to Helicobacter pylori. Gastroenterology. 2006; 130(6):1754-1763.
- [17]Mori N, Sato H, Hayashibara T, Senba M, Geleziunas R, Wada A et al.. Helicobacter pylori induces matrix metalloproteinase-9 through activation of nuclear factor kappaB. Gastroenterology. 2003; 124(4):983-992.
- [18]Wang Y, Wu H, Wu X, Bian Z, Gao Q. Interleukin 17A promotes gastric cancer invasiveness via NF-kappaB mediated matrix metalloproteinases 2 and 9 expression. PLoS One. 2014; 9(6):e96678.
- [19]Fridman R, Toth M, Pena D, Mobashery S. Activation of progelatinase B (MMP-9) by gelatinase A (MMP-2). Cancer Res. 1995; 55(12):2548-2555.
- [20]Liu J, Liu Q, Wan Y, Zhao Z, Yu H, Luo H et al.. Osteopontin promotes the progression of gastric cancer through the NF-kappaB pathway regulated by the MAPK and PI3K. Int J Oncol. 2014; 45(1):282-290.
- [21]Hashimoto I, Koizumi K, Tatematsu M, Minami T, Cho S, Takeno N et al.. Blocking on the CXCR4/mTOR signalling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells. Eur J Cancer. 2008; 44(7):1022-1029.
- [22]Das G, Shiras A, Shanmuganandam K, Shastry P. Rictor regulates MMP-9 activity and invasion through Raf-1-MEK-ERK signaling pathway in glioma cells. Mol Carcinog. 2011; 50(6):412-423.
- [23]Osman B, el Akool S, Doller A, Muller R, Pfeilschifter J, Eberhardt W. Differential modulation of the cytokine-induced MMP-9/TIMP-1 protease-antiprotease system by the mTOR inhibitor rapamycin. Biochem Pharmacol. 2011; 81(1):134-143.
- [24]Chung WC, Jung SH, Lee KM, Paik CN, Kawk JW, Jung JH et al.. The detection of Helicobacter pylori cag pathogenicity islands (PAIs) and expression of matrix metalloproteinase-7 (MMP-7) in gastric epithelial dysplasia and intramucosal cancer. Gastric Cancer. 2010; 13(3):162-169.
- [25]Wroblewski LE, Noble PJ, Pagliocca A, Pritchard DM, Hart CA, Campbell F et al.. Stimulation of MMP-7 (matrilysin) by Helicobacter pylori in human gastric epithelial cells: role in epithelial cell migration. J Cell Sci. 2003; 116(Pt 14):3017-3026.
- [26]Bergin PJ, Sicheng W, Qiang PH, Marianne QJ. Secretion of matrix metalloproteinase-9 by macrophages, in vitro, in response to Helicobacter pylori. FEMS Immunol Med Microbiol. 2005; 45(2):159-169.
- [27]Bebb JR, Letley DP, Thomas RJ, Aviles F, Collins HM, Watson SA et al.. Helicobacter pylori upregulates matrilysin (MMP-7) in epithelial cells in vivo and in vitro in a Cag dependent manner. Gut. 2003; 52(10):1408-1413.
- [28]Long ZW, Wang JL, Wang YN. Matrix metalloproteinase-7 mRNA and protein expression in gastric carcinoma: a meta-analysis. Tumour Biol. 2014; 35(11):11415-11426.
- [29]Shen W, Xi H, Wei B, Chen L. The prognostic role of matrix metalloproteinase 2 in gastric cancer: a systematic review with meta-analysis. J Cancer Res Clin Oncol. 2014; 140(6):1003-1009.
- [30]Byeon SJ, Han N, Choi J, Kim MA, Kim WH. Prognostic implication of TSC1 and mTOR expression in gastric carcinoma. J Surg Oncol. 2014; 109(8):812-817.
- [31]Tapia O, Riquelme I, Leal P, Sandoval A, Aedo S, Weber H et al.. The PI3K/AKT/mTOR pathway is activated in gastric cancer with potential prognostic and predictive significance. Virchows Arch. 2014; 465(1):25-33.