• 中國醫(yī)科大學(xué)附屬第一醫(yī)院普通外科教研室血管甲狀腺外科（沈陽 110001 ）;

【摘要】目的  探討表皮生長因子(epidermal growth factor, EGF)促進(jìn)胰腺癌細(xì)胞侵襲和轉(zhuǎn)移的分子機(jī)理。方法 EGF對(duì)胰腺癌細(xì)胞系NOR-P1的增殖、黏附及侵襲能力的影響分別用WST-1細(xì)胞增殖實(shí)驗(yàn)、細(xì)胞黏附實(shí)驗(yàn)和Transwell體外侵襲實(shí)驗(yàn)檢測；MMP-9和MMP-2的活性及表達(dá)分別用明膠酶譜分析和Western 印跡、RT-PCR檢測；NF-κB 活性用凝膠電泳遷移實(shí)驗(yàn)檢測。結(jié)果 EGF能夠明顯促進(jìn)胰腺癌細(xì)胞的侵襲能力，但對(duì)胰腺癌細(xì)胞的黏附力及增殖并無明顯影響；EGF明顯上調(diào)胰腺癌細(xì)胞的NF-κB和MMP-9的活性及表達(dá)，但對(duì)MMP-2活性及表達(dá)無影響；NF-κB抑制物四氫化吡咯二硫代氨基甲酸鹽(PDTC)能夠明顯抑制EGF所誘導(dǎo)的NF-κB活性，同時(shí)也抑制EGF所誘導(dǎo)的MMP-9表達(dá)及胰腺癌細(xì)胞的侵襲力。結(jié)論 EGF通過活化NF-κB促進(jìn)胰腺癌細(xì)胞的MMP-9的表達(dá)和侵襲力，采用NF-κB抑制劑PDTC阻斷NF-κB通路能夠降低胰腺癌細(xì)胞的侵襲力。

引用本文： 張浩,李昱驥,周建平,孔凡民,董明,郭克建. 表皮生長因子促進(jìn)胰腺癌細(xì)胞侵襲和轉(zhuǎn)移的實(shí)驗(yàn)研究. 中國普外基礎(chǔ)與臨床雜志, 2008, 15(3): 180-184. doi: 復(fù)制

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2. Garcea G, Neal CP, Pattenden CJ, et al.Molecular prognostic markers in pancreatic cancer: a systematic review [J]. Eur J Cancer, 2005; 41(15)∶2213.
3. Kolb A, Kleeff J, Arnold N, et al. Expression and differential signaling of heregulins in pancreatic cancer cells [J]. Int J Cancer, 2007; 120(3)∶514.
4. 董明， 周建平， 張浩， 等. 中國人與西方人胰腺癌組織中Ki-ras基因第12密碼子突變表型的比較[J]. 中國普外基礎(chǔ)與臨床雜志， 2006; 13（5）∶524.
5. Kayahara M, Nakagawara H, Kitagawa H, et al. The nature of neural invasion by pancreatic cancer [J]. Pancreas, 2007; 35(3)∶218.
6. Kleeff J, Beckhove P, Esposito I, et al. Pancreatic cancer microenvironment [J]. Int J Cancer, 2007; 121(4)∶699.
7. Tan X, Egami H, Nozawa F, et al. Analysis of the invasion-metastasis mechanism in pancreatic cancer: involvement of plasmin(ogen) cascade proteins in the invasion of pancreatic cancer cells [J]. Int J Oncol, 2006; 28(2)∶369.
8. Tan X, Egami H, Ishikawa S, et al. Involvement of matrix metalloproteinase-7 in invasion-metastasis through induction of cell dissociation in pancreatic cancer [J]. Int J Oncol, 2005; 26(5)∶1283.
9. Pryczynicz A, Guzińska-Ustymowicz K, Dymicka-Piekarska V, et al. Expression of matrix metalloproteinase 9 in pancreatic ductal carcinoma is associated with tumor metastasis formation [J]. Folia Histochem Cytobiol, 2007; 45(1)∶37.
10. Wang Z, Banerjee S, Li Y, et al. Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells [J]. Cancer Res, 2006; 66(5)∶2778.
11. Takada M, Hirata K, Ajiki T, et al. Expression of receptor for advanced glycation end products (RAGE) and MMP-9 in human pancreatic cancer cells [J]. Hepatogastroenterology, 2004; 51(58)∶928.
12. Harvey SR, Hurd TC, Markus G, et al. Evaluation of urinary plasminogen activator, its receptor, matrix metalloproteinase-9, and von Willebrand factor in pancreatic cancer [J]. Clin Cancer Res, 2003; 9(13)∶4935.
13. Duxbury MS, Whang EE. RRM2 induces NF-kappaB-dependent MMP-9 activation and enhances cellular invasiveness [J]. Biochem Biophys Res Commun, 2007; 354(1)∶190.
14. 張克君， 高焱明， 楊金鏞， 等. IκB-α基因轉(zhuǎn)染HCC9204細(xì)胞對(duì)NF-κB和MMP-9表達(dá)的影響[J]. 中國普外基礎(chǔ)與臨床雜志， 2006； 14（2）∶185.
15. Kajanne R, Miettinen P, Mehlem A, et al. EGF-R regulates MMP function in fibroblasts through MAPK and AP-1 pathways [J]. J Cell Physiol, 2007; 212(2)∶489.
16. Shiratsuchi T, Ishibashi H, Shirasuna K. Inhibition of epidermal growth factor-induced invasion by dexamethasone and AP-1 decoy in human squamous cell carcinoma cell lines [J]. J Cell Physiol, 2002; 193(3)∶340.
17. Cowden Dahl KD, Zeineldin R, Hudson LG. PEA3 is necessary for optimal epidermal growth factor receptor-stimulated matrix metalloproteinase expression and invasion of ovarian tumor cells [J]. Mol Cancer Res, 2007; 5(5)∶413.
  1. 1. 17 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.
  2. 2. Garcea G, Neal CP, Pattenden CJ, et al.Molecular prognostic markers in pancreatic cancer: a systematic review [J]. Eur J Cancer, 2005; 41(15)∶2213.
  3. 3. Kolb A, Kleeff J, Arnold N, et al. Expression and differential signaling of heregulins in pancreatic cancer cells [J]. Int J Cancer, 2007; 120(3)∶514.
  4. 4. 董明， 周建平， 張浩， 等. 中國人與西方人胰腺癌組織中Ki-ras基因第12密碼子突變表型的比較[J]. 中國普外基礎(chǔ)與臨床雜志， 2006; 13（5）∶524.
  5. 5. Kayahara M, Nakagawara H, Kitagawa H, et al. The nature of neural invasion by pancreatic cancer [J]. Pancreas, 2007; 35(3)∶218.
  6. 6. Kleeff J, Beckhove P, Esposito I, et al. Pancreatic cancer microenvironment [J]. Int J Cancer, 2007; 121(4)∶699.
  7. 7. Tan X, Egami H, Nozawa F, et al. Analysis of the invasion-metastasis mechanism in pancreatic cancer: involvement of plasmin(ogen) cascade proteins in the invasion of pancreatic cancer cells [J]. Int J Oncol, 2006; 28(2)∶369.
  8. 8. Tan X, Egami H, Ishikawa S, et al. Involvement of matrix metalloproteinase-7 in invasion-metastasis through induction of cell dissociation in pancreatic cancer [J]. Int J Oncol, 2005; 26(5)∶1283.
  9. 9. Pryczynicz A, Guzińska-Ustymowicz K, Dymicka-Piekarska V, et al. Expression of matrix metalloproteinase 9 in pancreatic ductal carcinoma is associated with tumor metastasis formation [J]. Folia Histochem Cytobiol, 2007; 45(1)∶37.
  10. 10. Wang Z, Banerjee S, Li Y, et al. Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells [J]. Cancer Res, 2006; 66(5)∶2778.
  11. 11. Takada M, Hirata K, Ajiki T, et al. Expression of receptor for advanced glycation end products (RAGE) and MMP-9 in human pancreatic cancer cells [J]. Hepatogastroenterology, 2004; 51(58)∶928.
  12. 12. Harvey SR, Hurd TC, Markus G, et al. Evaluation of urinary plasminogen activator, its receptor, matrix metalloproteinase-9, and von Willebrand factor in pancreatic cancer [J]. Clin Cancer Res, 2003; 9(13)∶4935.
  13. 13. Duxbury MS, Whang EE. RRM2 induces NF-kappaB-dependent MMP-9 activation and enhances cellular invasiveness [J]. Biochem Biophys Res Commun, 2007; 354(1)∶190.
  14. 14. 張克君， 高焱明， 楊金鏞， 等. IκB-α基因轉(zhuǎn)染HCC9204細(xì)胞對(duì)NF-κB和MMP-9表達(dá)的影響[J]. 中國普外基礎(chǔ)與臨床雜志， 2006； 14（2）∶185.
  15. 15. Kajanne R, Miettinen P, Mehlem A, et al. EGF-R regulates MMP function in fibroblasts through MAPK and AP-1 pathways [J]. J Cell Physiol, 2007; 212(2)∶489.
  16. 16. Shiratsuchi T, Ishibashi H, Shirasuna K. Inhibition of epidermal growth factor-induced invasion by dexamethasone and AP-1 decoy in human squamous cell carcinoma cell lines [J]. J Cell Physiol, 2002; 193(3)∶340.
  17. 17. Cowden Dahl KD, Zeineldin R, Hudson LG. PEA3 is necessary for optimal epidermal growth factor receptor-stimulated matrix metalloproteinase expression and invasion of ovarian tumor cells [J]. Mol Cancer Res, 2007; 5(5)∶413.