E-cadherin/Vimentin蛋白在胆管上皮细胞中表达的实验研究
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摘要
目的探讨上皮标志物E-cadherhin蛋白和间叶标志物Vimentin蛋白在LPS诱导的胆管上皮细胞中的表达及其意义。方法选用SD大鼠和人肝内胆管上皮细胞作为研究对象,用内毒素(LPS 2ug/ml)刺激胆管上皮细胞,分别用免疫组化、Western blotting检测E-cadherin和Vimentin蛋白的表达情况。结果SD大鼠肝内胆管上皮细胞经LPS刺激后,E-cadherin蛋白表达缺失,且与诱导时间呈正相关(P<0.01),而Vimentin蛋白则出现阳性表达(P<0.05)；人肝内胆管上皮细胞经LPS刺激后胆管上皮细胞形态发生改变,细胞免疫组化检测发现E-cadherin蛋白表达下调,Vimentin蛋白表达上调(P<0.01), Western Blotting检测与免疫组织化学检测结果一致。
结论LPS刺激胆管上皮细胞,能使胆管上皮细胞中上皮性标志物E-cadherin表达缺失或下调,而间叶性标志物Vimentin表达阳性或上调,说明LPS刺激可使胆管上皮细胞发生上皮-间叶样表型转化(EMT)。
Objective:Exploring the expression and importance of epithelial marker E-cadherhin and mesenehymal marker Vimentin in the bile duct epithelial cells which induced by LPS.Methods:We choose SD rats and the normal cells of human intrahepatic bile ducts epithelial as researchobject. Take the researchobject put into LPS(2ug/ml),we use immunohistochemical and Western Blotting technique in detecting both the markers of epithelial E-cadherin and mesenehymal Vimentin. Results:Animal experiments,We found E-cadherin gradually reduced (P<0.01) and Vimentin acquired masculine expression after induction (P<0.05). Cells experiments,the cell morphology of BEC happened mesenchymal after induction. By immunohistochemical detection we also found epithelial E-cadherin gradually reduced and Vimentin acquired masculine expression after induction (P<0.01). As to as Western Blotting results.
Conclusion:E-cadherin gradually reduced and Vimentin acquired masculine expression in the bile duct epithelial cells after induction.That means epithelial-mesenehymal transitions had happened in the bile duct epithelial cells which inducted by LPS.
结论LPS刺激胆管上皮细胞,能使胆管上皮细胞中上皮性标志物E-cadherin表达缺失或下调,而间叶性标志物Vimentin表达阳性或上调,说明LPS刺激可使胆管上皮细胞发生上皮-间叶样表型转化(EMT)。
Objective:Exploring the expression and importance of epithelial marker E-cadherhin and mesenehymal marker Vimentin in the bile duct epithelial cells which induced by LPS.Methods:We choose SD rats and the normal cells of human intrahepatic bile ducts epithelial as researchobject. Take the researchobject put into LPS(2ug/ml),we use immunohistochemical and Western Blotting technique in detecting both the markers of epithelial E-cadherin and mesenehymal Vimentin. Results:Animal experiments,We found E-cadherin gradually reduced (P<0.01) and Vimentin acquired masculine expression after induction (P<0.05). Cells experiments,the cell morphology of BEC happened mesenchymal after induction. By immunohistochemical detection we also found epithelial E-cadherin gradually reduced and Vimentin acquired masculine expression after induction (P<0.01). As to as Western Blotting results.
Conclusion:E-cadherin gradually reduced and Vimentin acquired masculine expression in the bile duct epithelial cells after induction.That means epithelial-mesenehymal transitions had happened in the bile duct epithelial cells which inducted by LPS.
引文
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2. Savager P. Leaving the neighborhood:molecular mechanisms involved during epithelial-mesenchymal transition.Bioessays,2001,23:912-923.
3. Rygiell KA, Robertsonl H, Marshalll HL,et al. Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease[J]. Laboratory Investigation,2008,88:112-123.
4. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2:442-54.
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6. Gilles C, Polette Molette M, Mestdagt M,et al.Transactivation of vimentin by beta-catenin in human breast cancer cells.Cancer Res,2003,63(10):2658-2664.
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12. Cholangiocytes with mesenchymal features contribute to progressive hepatic fibrosis of the polycystic kidney rat.Sato,-Y; Harada,-K; Ozaki,-S; Furubo,-S; Kizawa,-K; Sanzen,-T; Yasoshima,-M; Ikeda,-H; Sasaki,-M; Nakanuma,-Y SO:Am-J-Pathol. 2007 Dec; 171(6):1859-71.
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2. Savager P. Leaving the neighborhood:molecular mechanisms involved during epithelial-mesenchymal transition.Bioessays,2001,23:912-923.
3. Rygiell KA, Robertsonl H, Marshalll HL,et al. Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease[J]. Laboratory Investigation,2008,88:112-123.
4. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2:442-54.
5. Spath GF, Weiss MC. Hepatocyte nuclear factor 4 provokes expression of epithelial marker genes, acting as a morphogen in dedifferentiated hepatoma cells, J Cell Biol, 1998,140(4),935-46.
6. Gilles C, Polette Molette M, Mestdagt M,et al.Transactivation of vimentin by beta-catenin in human breast cancer cells.Cancer Res,2003,63(10):2658-2664.
7. Ho-Soon,Choi,M.D,Christopher E,Savard,M.S,et al.Paclitaxel Interrupts TGF-β1 Signaling Between Gallbladder Epithelial Cell and Myofibroblasts.Journal of Surgical Research 141,May 17,2006,pages 183-191.
8. Helen Robertson,John A.Kirby.et al.biliary epithelial-mesenchymal transition in posttransplantation recurrence of primary biliary cirrhosis [J]. Journal of Surgical ResearchVolume 141, Issue 2, August 2007, Pages 183-191.
9.苏钢强,徐志海等,实验动物学,科学出版社,2007.08(6)78-96.
10.周庚寅,组织病理学技术,北京大学医学出版社,2006(3)112-146.
11. Shi YY,Nacamuli RP,Salim A,et al.The osteogenic potential of adipose-derived mesenchymal cells is maintained with aging.Plast Reconstr Surg.2005,116(16):1686-1696.
12. Cholangiocytes with mesenchymal features contribute to progressive hepatic fibrosis of the polycystic kidney rat.Sato,-Y; Harada,-K; Ozaki,-S; Furubo,-S; Kizawa,-K; Sanzen,-T; Yasoshima,-M; Ikeda,-H; Sasaki,-M; Nakanuma,-Y SO:Am-J-Pathol. 2007 Dec; 171(6):1859-71.
13. Vincan E, Brabletz T, Faux MC, et al. A human three-dimensional cell line model allows the study of dynamic and reversible epithelial-mesenchymal and mesenchymal-epithelial transition that underpins colorectal carcinogenesis[J]. Cells Tissues Organs,2007,185(1):20-8.
1. Rygiell KA, Robertson1 H, Marshall1 HL,et al. Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease[J].Laboratory Investigation,2008,88:112-123.
2. Strutz F,Okada H, Neilson EG The role of the tubular epithelial cell in renal fibrogenesis Clin Exp Nephrol 2001,5:62-74.
3. Nakayama H, Scott IC, Cross JC. The transition to endoreduplication in trophoblast giant cells is regulated by the mRNA zinc finger transcription factor. Dev Biol, 1998,199:150-163.
4. Auersperg N, Pan J, Grove BD, et al. E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium. Proc Natl Acad Sci U S A.1999 May 25;96(11):6249-54.
5. Petersen OW, Nielsen HL, Gudjonsson T, Villadsen R,et al:Epithelial- to-mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am J Pathol 2003,162:391-402.
6. Eitner F, Floege J:Novel insights into renal fibrosis. Curr Opin Nephrol Hypertens2003,12:227-232.
7. Iwano, M., D. Plieth, T.M. Danoff, C. et al. Evidence that fi broblasts derive from epithelium during tissue fibrosis. J. Clin. Invest.2002,110:341-350.
8. Nishitani, Y., M. Iwano, Y. Yamaguchi, K. et al.2005. Fibroblast-specifi c protein 1 is a specific prognostic marker for renal survival in patients with IgAN. Kidney Int. 68:1078-1085.
9. Gong DW, He YF, KaeasM, et al. Uncoup ling p rotein 3 is a mediator of thermogenesis regulated by thyroid hormone, beta3-adrenergic agonists, and lep tin [J]. J Biol Chem,1997,272(39):24129-24132.
10. Clapham JC, Arch JR, Chapman H, et al. Mice over exp ressing human uncoup ling p rotein 3 in skeletal muscle are hyperphagic and lean[J]. Nature,2000,406 (6794) 4152418.
11. Lan HY:Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells. Curr Opin Nephrol Hypertens 2003,12:25-29.
12. Yanez-Mo M, Lara-Pezzi E, Selgas R, Ramirez-Huesca M, et al.:Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells. N Engl J Med 2003,348:403-413.
13. Pollack V, Sarkozi R, Banki Z, et al. Oncostatin M-induced effects on EMT in human proximal tubular cells:differential role of ERK signaling[J]. Am J Physiol Renal Physiol,2007,293(5):,1714-26.
14. Gressner AM,Weiskirchen R,Breitkopf K,et al.Roles of TGF-beta in hepatic fibrosis.Front Biosci,2002,7:793-807.
15. Flanders KC. Smad3 as a mediator or of the fibrotic response.Int Exp Path,2004,85(2):47-64.
16. Massague RP, Wotton D.Transcriptional control by the TGF-β1/smad signaling system [J]. EMBO,2000,19:1745.
17. Heldin CH,Miyazono K,Dijke P. TGF-betal signaling from cell membrane to nucleus through smad proteins [J]. Nature,1997,390:465.
18. Ho-Soon Choi, Christopher E. et al. Paclitaxel interrupts TGF-betal signaling between gallbladder epithelial cells and myofibroblasts. Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington.98195, USA. J Surg Res.2007 Aug;141(2):183-91. Epub 2007 Jun 14.
19. Ray M E, Mehra R, Sandler H M, et al E-cadherin protein expression predicts prostate cancer salvage radiotherapy outcomes [J]. JUrol,2006,176(4pt I):1409-1414.
20. Roberts AB,Russo A, Felici A, et al.Smad3:a key player in pathogenetic mechanisms dependent on TGF-beta. Ann NY Acad Sci,2003,995:1-10].
21. Stroschein SL,Wang W,LuoKX.Cooperative binding of Smad proteins to two adjacent DNA elements in the plasminogen activator inhitor-1 promoter mediates transforming growth factor P-induced smad-dependent transcriptional activation.J Biol Chem,1999,274(14):9431-9441.
22. Christofori G. New signals from the invasive front [J]. Nature,2006,441 (7092): 444-450.
23. HuberMA, Beug H, Wirth T. Ep ithelial-mesenchymal transition:NF-κB takes center stage [J]. Cell Cycle,2004,3(12):1477-1480.
24. Thiery JP. Ep ithelial-mesenchymal transitions in tumour p rogres-sion[J]. Nat Rev Cancer,2002,2 (6):442-454.
25. GuarinoM. Ep ithelial-mesenchymal transition and tumour invasion[J]. Int J Biochem Cell Biol,2007,39 (12):2153-2160.
26. Christiansen JJ, Rajasekaran AK. Reassessing ep ithelial to mesen-chymal transition as a p rerequisite for carcinoma invasion and me-tastasis[J]. Cancer Res,2006,66 (17):8319-8326.
27. Radisky DC, Kenny PA, BissellMJ. Fibrosis and cancer:domyo-fibroblasts come also from ep ithelial cells via EMT[J]. J CellBio-chem,2007,101 (4):830-839.
28. Thiery JP:Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003,15:740-746.
29. Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival:implications in development and cancer. Development,2005 Jul; 132(14):3151-61.
30. Brabletz T, Hlubek F, Spaderna S, et al. Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin. Cells Tissues Organs.2005;179(1-2):56-65.
31. Liebner S, Cattelino A, Gallini R, et al. P-catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse. J Cell Biol2004,166:359-367.
32. Xue C, Plieth D, Venkov C, Xu C, Neilson EG:The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis. Cancer Res2003,63:3386-3394.
33. Brabletz T, Hlubek F, Spaderna S, et al. Invasion and metastasis in colorectal cancer: ep ithelial-mesenchymal transition, mesenchy-mal-ep ithelial transition,stem cells and beta-catenin [J]. CellsTissuesOrgans,2005,179 (122):56-65.
34. Zavadil J, Bottinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene.2005 Aug 29;24(37):5764-74.
35. Janda E, Lehmann K, Killisch I, et al:Ras and TGFb cooperatively regulate epithelial cell plasticity and metastasis:dissection of Ras signaling pathways. J Cell Biol 2002,156:299-313.
36. Peinado, H., Quintanilla, M., and Cano, A. Transforming growth factor beta-1 induces Snail transcription factor in epithelial cell lines:implications for epithelial mesenchymal transitions. Oncogene,2003,23,21113-21123.
37. Janda, E., Lehmann, K., Killisch, I., et al. Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis:dissection of Ras signaling pathways. J. Cell Biol.2002,156,299-313.
38. Ozdamar, B., Bose, R., Barrios-Rodiles, M., et al. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science.2005,307, 1603-1609.
39. Gotzmann J, Fischer AN, Zojer M, et al. A crucial function of PDGF in TGF-beta-mediated cancer progression of hepatocytes. Oncogene.2006 May 25;25(22):3170-85.
40. Inoue, A., Seidel, M. G., Wu, W., Kamizono, S., et al. Slug, a highly conserved zinc finger Transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo. Cancer Cell,2002,2,279-288.
41. Janda E, Lehmann K, Killisch I, et al:Ras and TGFb cooperatively regulate epithelial cell plasticity and metastasis:dissection of Ras signaling pathways. J Cell Biol 2002,156:299-313.
42. Grille SJ, Bellacosa A, Upson J, et al:The protein kinase akt induces epithelial-mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res 2003,63:2172-2178.
43. Cheng C W, Wu P E, Yu J C, et al. Mechanisms of inactiva-tion of E-cadherin in breast carcinoma:modification of the twohit hypothesis of tumor suppressor gene [J]. Oncogene,2001,20:3814.
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