Epidermal Growth Factor-Mediated NF-κB Activity Induces Matrix Metalloproteinase-9 Expression and Invasion in Pancreatic Cancer Cell_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIU Yu ¹ , ZHANG Hao ² , YANG Ye ¹ , WANG Xin ¹ , LI Tiemin ¹ , GUO Renxuan ²

1.Department of Geriatric Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, China;;
2.Department of General Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110001, China;

Corresponding author：

Keywords：

Epidermal growth factor; Pancreatic cancer; Matrix metalloproteinases; Nuclear factor-κB; Invasion; Metastasis

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Objective To observe the effect of epidermal growth factor (EGF) on the proliferation, adhesion, invasiveness and the activation of nuclear factor-κB (NF-κB), matrix metalloproteinases (MMPs) expression and explore related mechanisms in pancreatic cancer cells.
Methods Cell invasion assay, proliferation assay and adhesion assay were used to examine the proliferation, adhesion and invasiveness of pancreatic cancer cells, respectively. NF-κB activity was detected by electrophoretic mobility shift assay (EMSA), and MMPs protein and mRNA expressions were investigated by gelatin zymography, Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR).
Results EGF increased the invasiveness of pancreatic cancer cell in a dose-dependent manner (P＜0.05), but did not affect cell proliferation or adhesion. The expressions of MMP-9 mRNA and protein significantly increased after induction by EGF and were highest when EGF concentration was 50 ng/ml, while there was no effect on the expressions of MMP-2 mRNA and protein. Furthermore, NF-κB activity increased with increased concentration of EGF in a concentration-dependent manner (P＜0.05). In addition, NF-κB activity and the expressions of MMP-9 mRNA and protein by pretreatment with both pyrrolidine dithiocarbamate (PDTC) and EGF decreased when compared that by pretreatment with EGF alone. The invasiveness of pancreatic cancer cell by pretreatment with both PDTC and EGF decreased when compared that by pretreatment with EGF alone and nothing (P＜0.05).
Conclusion The findings indicate that the NF-κB-mediated MMP-9 induction is essential for EGF-induced invasiveness in pancreatic cancer cells, which can be inhibited by PDTC.

Citation： LIU Yu ,ZHANG Hao,YANG Ye,WANG Xin,LI Tiemin,GUO Renxuan. Epidermal Growth Factor-Mediated NF-κB Activity Induces Matrix Metalloproteinase-9 Expression and Invasion in Pancreatic Cancer Cell. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2009, 16(8): 603-608. doi: Copy

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2.	张浩, 李昱骥, 周建平, 等. 表皮生长因子促进胰腺癌细胞侵袭和转移的实验研究 [Ｊ]. 中国普外基础与临床杂志, 2008; 15(3): 180-184.
3.	Felx M, Guyot MC, Isler M, et al. Endothelin-1 (ET-1) promotes MMP-2 and MMP-9 induction involving the transcription factor NF-κB in human osteosarcoma [Ｊ]. Clin Sci (Lond), 2006; 110(6): 645-654.
4.	Katoh M, Katoh M. Transcriptional mechanisms of WNT5A based on NF-κB, Hedgehog, TGFβ, and Notch signaling cascades [Ｊ]. Int J Mol Med, 2009; 23(6): 763-769.
5.	陆颖影, 靖大道, 王兴鹏. 表皮生长因子受体与胰腺癌的关系及以其为靶向治疗的研究进展 [Ｊ]. 胃肠病学, 2007; 12(1): 53-55.
6.	陈宗静, 童赛雄. 表皮生长因子受体家族在胰腺癌与壶腹癌中表达情况的研究现状 [Ｊ]. 肝胆胰外科杂志, 2004; 16(1): 76-77.
7.	陆澄, 曾水林, 张郢华, 等. 胰腺癌组织中P21(WAF1)、转化生长因子α、表皮生长因子受体表达与神经浸润转移的关系 [Ｊ]. 南通大学学报（医学版）, 2006; 26(1): 31-32.
8.	Festuccia C, Angelucci A, Gravina GL, et al. Epidermal growth factor modulates prostate cancer cell invasiveness regulating urokinase-type plasminogen activator activity. EGF-receptor inhibition may prevent tumor cell dissemination [Ｊ]. Thromb Haemost, 2005; 93(5): 964-975.
9.	Banerjee S, Sengupta K, Saxena NK, et al. Epidermal gr-owth factor induces WISP-2/CCN5 expression in estrogen receptor-positive breast tumor cells through multiple molecular cross-talks [Ｊ]. Mol Cancer Res, 2005; 3(3): 151-162.
10.	Nakatsuji Y, Nishio Y, Tani N, et al. Epidermal growth factor enhances invasive activity of BeWo choriocarcinoma cells by inducing 2 integrin expression [Ｊ]. Endocr J, 2003; 50(6): 703-714.
11.	Nagai S, Nakamura M, Yanai K, et al. Gli1 contributes to the invasiveness of pancreatic cancer through matrix metalloproteinase-9 activation [Ｊ]. Cancer Sci, 2008; 99(7): 1377-1384.
12.	Uchima Y, Sawada T, Hirakawa K. Action of antiproteases on pancreatic cancer cells [Ｊ]. JOP， 2007; 8(4 Suppl): 479-487.
13.	Ellenrieder V, Hendler SF, Ruhland C, et al. TGF-β-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator system [Ｊ]. Int J Cancer, 2001; 93(2): 204-211.
14.	肖敏, 陈婕, 余晓云, 等. Angiopoietin-2, MMP-9和TIMP-1在胰腺癌中的表达及其与胰腺癌侵袭转移的关系 [Ｊ]. 临床消化病杂志, 2006; 18(4): 216-218.
15.	Tamahashi U, Kumagai J, Takizawa T, et al. Expression and intracellular localization of matrix metalloproteinases in intraductal papillary mucinous neoplasms of the pancreas [Ｊ]. Virchows Arch, 2008; 453(1): 79-87.
16.	张克君, 李德春, 高焱明, 等. NF-κB、 MMP-9与肝细胞肝癌浸润转移的实验研究 [Ｊ]. 中华肝胆外科杂志, 2006; 12(10): 691-694.
17.	张东涛, 杨力, 郭新宁, 等. 核因子-κB和MMP-9与胃癌侵袭转移的关系 [Ｊ]. 肿瘤防治杂志， 2004; 11(6): 566-568.
18.	Rhee JW, Lee KW, Sohn,WJ, et al. Regulation of matrix metalloproteinase-9 gene expression and cell migration by NF-κB in response to CpG-oligodeoxynucleotides in RAW 264.7 cells [Ｊ]. Mol Immunol, 2007; 44(6): 1393-1400.
19.	Sliva D, English D, Lyons D, et al. Protein kinase C induces motility of breast cancers by upregulating secretion of urokinase-type plasminogen activator through activation of AP-1 and NF-κB [Ｊ]. Biochem Biophys Res Commun, 2002; 290(1): 552-557.
20.	Alaniz L, García M, Cabrera P, et al. Modulation of matrix metalloproteinase-9 activity by hyaluronan is dependent on NF-κB activity in lymphoma cell lines with dissimilar invasive behavior [Ｊ]. Biochem Biophys Res Commun, 2004; 324(2): 736-743.
21.	Zhang H, Ma G, Dong M, et al. Epidermal growth factor promotes invasiveness of pancreatic cancer cells through NF-κB-mediated proteinase productions [Ｊ]. Pancreas, 2006; 32(1): 101-109.
22.	张克君, 高焱明, 杨金镛, 等. IκB-α基因转染HCC9204细胞对NF-κB和MMP-9表达的影响 [Ｊ]. 中国普外基础与临床杂志, 2007; 14(2): 185-187.
23.	Watabe T, Yoshida K, Shindoh M, et al. The Ets-1 and Ets-2 transcription factors activate the promoters for invasion-associated urokinase and collagenase genes in response to epidermal growth factor [Ｊ]. Int J Cancer, 1998; 77(1): 128-137.
24.	Hahne JC, Okuducu AF, Sahin A, et al. The transcription factor ETS-1: its role in tumour development and strategies for its inhibition [Ｊ]. Mini Rev Med Chem, 2008; 8(11): 1095-1105.
25.	Kim S, Choi JH, Kim JB, et al. Berberine suppresses TNF-α-induced MMP-9 and cell invasion through inhibition of AP-1 activity in MDA-MB-231 human breast cancer cells [Ｊ]. Molecules, 2008; 13(12): 2975-2985.

1. Farrow B, Sugiyama Y, Chen A, et al. Inflammatory mechanisms contributing to pancreatic cancer development [Ｊ]. Ann Surg, 2004; 239(6): 763-771.
2. 张浩, 李昱骥, 周建平, 等. 表皮生长因子促进胰腺癌细胞侵袭和转移的实验研究 [Ｊ]. 中国普外基础与临床杂志, 2008; 15(3): 180-184.
3. Felx M, Guyot MC, Isler M, et al. Endothelin-1 (ET-1) promotes MMP-2 and MMP-9 induction involving the transcription factor NF-κB in human osteosarcoma [Ｊ]. Clin Sci (Lond), 2006; 110(6): 645-654.
4. Katoh M, Katoh M. Transcriptional mechanisms of WNT5A based on NF-κB, Hedgehog, TGFβ, and Notch signaling cascades [Ｊ]. Int J Mol Med, 2009; 23(6): 763-769.
5. 陆颖影, 靖大道, 王兴鹏. 表皮生长因子受体与胰腺癌的关系及以其为靶向治疗的研究进展 [Ｊ]. 胃肠病学, 2007; 12(1): 53-55.
6. 陈宗静, 童赛雄. 表皮生长因子受体家族在胰腺癌与壶腹癌中表达情况的研究现状 [Ｊ]. 肝胆胰外科杂志, 2004; 16(1): 76-77.
7. 陆澄, 曾水林, 张郢华, 等. 胰腺癌组织中P21(WAF1)、转化生长因子α、表皮生长因子受体表达与神经浸润转移的关系 [Ｊ]. 南通大学学报（医学版）, 2006; 26(1): 31-32.
8. Festuccia C, Angelucci A, Gravina GL, et al. Epidermal growth factor modulates prostate cancer cell invasiveness regulating urokinase-type plasminogen activator activity. EGF-receptor inhibition may prevent tumor cell dissemination [Ｊ]. Thromb Haemost, 2005; 93(5): 964-975.
9. Banerjee S, Sengupta K, Saxena NK, et al. Epidermal gr-owth factor induces WISP-2/CCN5 expression in estrogen receptor-positive breast tumor cells through multiple molecular cross-talks [Ｊ]. Mol Cancer Res, 2005; 3(3): 151-162.
10. Nakatsuji Y, Nishio Y, Tani N, et al. Epidermal growth factor enhances invasive activity of BeWo choriocarcinoma cells by inducing 2 integrin expression [Ｊ]. Endocr J, 2003; 50(6): 703-714.
11. Nagai S, Nakamura M, Yanai K, et al. Gli1 contributes to the invasiveness of pancreatic cancer through matrix metalloproteinase-9 activation [Ｊ]. Cancer Sci, 2008; 99(7): 1377-1384.
12. Uchima Y, Sawada T, Hirakawa K. Action of antiproteases on pancreatic cancer cells [Ｊ]. JOP， 2007; 8(4 Suppl): 479-487.
13. Ellenrieder V, Hendler SF, Ruhland C, et al. TGF-β-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator system [Ｊ]. Int J Cancer, 2001; 93(2): 204-211.
14. 肖敏, 陈婕, 余晓云, 等. Angiopoietin-2, MMP-9和TIMP-1在胰腺癌中的表达及其与胰腺癌侵袭转移的关系 [Ｊ]. 临床消化病杂志, 2006; 18(4): 216-218.
15. Tamahashi U, Kumagai J, Takizawa T, et al. Expression and intracellular localization of matrix metalloproteinases in intraductal papillary mucinous neoplasms of the pancreas [Ｊ]. Virchows Arch, 2008; 453(1): 79-87.
16. 张克君, 李德春, 高焱明, 等. NF-κB、 MMP-9与肝细胞肝癌浸润转移的实验研究 [Ｊ]. 中华肝胆外科杂志, 2006; 12(10): 691-694.
17. 张东涛, 杨力, 郭新宁, 等. 核因子-κB和MMP-9与胃癌侵袭转移的关系 [Ｊ]. 肿瘤防治杂志， 2004; 11(6): 566-568.
18. Rhee JW, Lee KW, Sohn,WJ, et al. Regulation of matrix metalloproteinase-9 gene expression and cell migration by NF-κB in response to CpG-oligodeoxynucleotides in RAW 264.7 cells [Ｊ]. Mol Immunol, 2007; 44(6): 1393-1400.
19. Sliva D, English D, Lyons D, et al. Protein kinase C induces motility of breast cancers by upregulating secretion of urokinase-type plasminogen activator through activation of AP-1 and NF-κB [Ｊ]. Biochem Biophys Res Commun, 2002; 290(1): 552-557.
20. Alaniz L, García M, Cabrera P, et al. Modulation of matrix metalloproteinase-9 activity by hyaluronan is dependent on NF-κB activity in lymphoma cell lines with dissimilar invasive behavior [Ｊ]. Biochem Biophys Res Commun, 2004; 324(2): 736-743.
21. Zhang H, Ma G, Dong M, et al. Epidermal growth factor promotes invasiveness of pancreatic cancer cells through NF-κB-mediated proteinase productions [Ｊ]. Pancreas, 2006; 32(1): 101-109.
22. 张克君, 高焱明, 杨金镛, 等. IκB-α基因转染HCC9204细胞对NF-κB和MMP-9表达的影响 [Ｊ]. 中国普外基础与临床杂志, 2007; 14(2): 185-187.
23. Watabe T, Yoshida K, Shindoh M, et al. The Ets-1 and Ets-2 transcription factors activate the promoters for invasion-associated urokinase and collagenase genes in response to epidermal growth factor [Ｊ]. Int J Cancer, 1998; 77(1): 128-137.
24. Hahne JC, Okuducu AF, Sahin A, et al. The transcription factor ETS-1: its role in tumour development and strategies for its inhibition [Ｊ]. Mini Rev Med Chem, 2008; 8(11): 1095-1105.
25. Kim S, Choi JH, Kim JB, et al. Berberine suppresses TNF-α-induced MMP-9 and cell invasion through inhibition of AP-1 activity in MDA-MB-231 human breast cancer cells [Ｊ]. Molecules, 2008; 13(12): 2975-2985.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Epidermal Growth Factor-Mediated NF-κB Activity Induces Matrix Metalloproteinase-9 Expression and Invasion in Pancreatic Cancer Cell

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