Effects of Gefitinib on Expression of Epidermal Growth Factor Receptor in Bile Duct Epithelial Cells and Its Significance_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WU Xingwu ¹ , XU Liang ² , QIN Yu ³ , HOU Changying ³ , XU Maolin ³ , LI Fuyu ⁴

1.The Third Department of Surgery, The Second People’s Hospital of Shuangliu County, Chengdu 610200, China;;
2.Department of General Surgery， Affiliated Hospital of Luzhou Medical College， Luzhou 646000, Sichuan Province, China;;
3.Department of General Surgery, The First People’s Hospital of Shuangliu County, Chengdu 610200, China;;
4.Department of Hepatobiliary Surgery, West China Hospital, Sichuan University, Chengdu 610041, China;

Corresponding author：

Keywords：

Hepatolithiasis; Gefitinib; Epidermal growth factor receptor; Bile duct epithelial cell; Chronic proliferative cholangitis; Immunohistochemistry; Real-time polymerase chain reaction

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Objective To observe the effect of gefitinib on expression of epidermal growth factor receptor (EGFR) in bile duct epithelial cells, and the feasibility of inhibiting hyperplasia of bile duct epithelial cells with gefitinib.
Methods Sixty-one patients with hepatolithiasis having to be in hospital for surgery from the First People’s Hospital of Shuangliu county were selected, with 25-65 years old, average 46.92 years. The patients were randomly divided into therapy group and control group. There were 30 cases in therapy group, in which fine duct was placed on lesion bile duct during operation, and through whom gefitinib solution was perfused after operation. There were 31 cases in control group with only T tube drainage after operation. The bile duct sample was obtained respectively during the operation and 6 weeks and 12 weeks after operation. The histology and expression change of EGFR were observed by HE staining, immunohistochemistry and RT-PCR method respectively.
Results There were no significant differences in pathohistology changes of bile duct and the EGFR protein and mRNA expression between therapy group and control group during operation. The hyperplasia of epithelium mucosae and submucosal gland in the therapy group were obviously decreased as compared with those in control group, the EGFR mRNA and protein expression in therapy group were weaker than those of control group （P lt;0.05） 6 weeks and 12 weeks after gefitinib treatment.
Conclusion EGFR is overexpressed in the chronic proliferative cholangitis, and continuously local application of gefitinib after operation can specifically interrupt the activation and expression of EFGR and then effectively inhibit the hyperplasia of bile duct epithelial cells.

Citation： WU Xingwu ,XU Liang,QIN Yu,HOU Changying,XU Maolin,LI Fuyu. Effects of Gefitinib on Expression of Epidermal Growth Factor Receptor in Bile Duct Epithelial Cells and Its Significance. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2010, 17(5): 469-473. doi: Copy

1.	Mok T, Wu YL, Zhang L. A small step towards personalized medicine for non-small cell lung cancer [J]. Discov Med, 2009; 8(43): 227-231.
2.	Chu Q, Amano O, Kanda Y, et al. Tumor-specific Cytotoxicity and Type of Cell Death Induced by Gefitinib in Oral Squamous Cell Carcinoma Cell Lines [J]. Anticancer Res, 2009; 29(12): 5023-5031.
3.	Yang CT, Hung JY, Lai CL, et al. Gefitinib as first-line therapy for advanced or metastatic non-small cell lung cancer patients in Southern Taiwan [J]. Kaohsiung J Med Sci, 2010; 26(1): 1-7.
4.	Herbst RS, Fukuoka M, Baselga J. Gefitinib－a novel targeted approach to treating cancer [J]. Nat Rev Cancer, 2004; 4(12): 956-965.
5.	Yoon JH, Gwak GY, Lee HS, et al. Enhanced epidermal growth factor receptor activation in human cholangiocarcinoma cells [J]. J Hepatol, 2004; 41(5): 808-814.
6.	Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase Ⅲ trial－INTACT 1 [J]. J Clin Oncol, 2004; 22(5): 777-784.
7.	Hwang JH, Yoon YB, Kim YT, et al. Risk factors for recurrent cholangitis after initial hepatolithiasis treatment [J]. J Clin Gastroenterol, 2004; 38(4): 364-367.
8.	Terada T, Nakanuma Y. Pathologic observations of intrahepatic peribiliary glands in 1 000 consecutive autopsy livers: Ⅳ. Hyperplasia of intramural and extramural glands [J]. Hum Pathol, 1992; 23(5): 483-490.
9.	Terada T, Nakanuma Y. Innervation of intrahepatic bile ducts and peribiliary glands in normal human livers, extrahepatic biliary obstruction and hepatolithiasis. An immunohistochemical study [J]. J Hepatol, 1989; 9(2): 141-148.
10.	Lu S, Yan L, Rao L, Xia T, et al. Down stream involvement of the bile duct in hepatolithiasis [J]. Chin Med J (Engl), 2002; 115(1): 62-64.
11.	Uchiyama K, Kawai M, Ueno M, et al. Reducing residual and recurrent stones by hepatectomy for hepatolithiasis [J]. J Gastrointest Surg, 2007; 11(5): 626-630.
12.	货师鹏. 受体研究技术 [M]. 北京: 北京大学医学出版社, 2004: 275-277.
13.	Schlessinger J. Cell signaling by receptor tyrosine kinases [J]. Cell, 2000; 103(2): 211-225.
14.	Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network [J]. Nat Rev Mol Cell Biol, 2001; 2(2): 127-137.
15.	Hackel PO, Zwick E, Prenzel N, et al. Epidermal growth factor receptors: critical mediators of multiple receptor pathways [J]. Curr Opin Cell Biol, 1999; 11(2): 184-189.
16.	Moghal N, Sternberg PW. Multiple positive and negative regulators of signaling by the EGF-receptor [J]. Curr Opin Cell Biol, 1999; 11(2): 190-196.
17.	Ishii M, Vroman B, LaRusso NF. Morphologic demonstration of receptor-mediated endocytosis of epidermal growth factor by isolated bile duct epithelial cells [J]. Gastroenterology, 1990; 98(5 Pt 1): 1284-1291.
18.	Van Winkle LS, Isaac JM, Plopper CG. Distribution of epidermal growth factor receptor and ligands during bronchiolar epithelial repair from naphthalene-induced Clara cell injury in the mouse [J]. Am J Pathol, 1997; 151(2): 443-459.
19.	Giaccone G. HER1/EGFR-targeted agents: predicting the future for patients with unpredictable outcomes to therapy [J]. Ann Oncol, 2005; 16(4): 538-548.
20.	Hamdi MM, Mutungi GM. Dihydrotestosterone activates the mitogen activated protein kinase pathway and modulates maximum isometric force in isolated intact mouse skeletal muscle fibres through the epidermal growth factor receptor [J]. J Physiol [Epub ahead of print]. PMID: 20008468. doi: 10.1113/jphysiol.2009.182162.
21.	Kondratov KA, Chernorudskiy AL, Amosova AP, et al. Termination of tyrphostin AG1478 application results in different recovery of EGF receptor tyrosine residues 1 045 and 1 173 phosphorylation in A431 cells [J]. Cell Biol Int, 2010; 34(1): 81-87.
22.	Donnellan F, Keating N, Geoghegan P, et al. JNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells [J]. Am J Physiol Gastrointest Liver Physiol, 2009 Oct 29[Epub ahead of print]. PMID: 19875701.
23.	正文, 朱明才, 汤为学, 等. 金雀异黄素与5-氟尿嘧啶对SGC-7901 细胞的抑制作用 [J]. 中国普外基础与临床杂志, 2008； 15（1）： 17-22.
24.	李龙, 岳红梅, 余勤. 表皮生长因子受体抑制剂与肺纤维化 [J]. 国外医学呼吸系统分册, 2005; 25(5): 345-348.
25.	龙怀聪, 王曾礼. 表皮生长因子受体拮抗剂对气道上皮细胞生长及修复的影响 [J]. 四川大学学报(医学版), 2003; 34(2): 254-256.
26.	Fan ST, Choi TK, Lo CM, et al. Treatment of hepatolithiasis: improvement of result by a systematic approach [J]. Surgery, 1991; 109(4): 474-480.
27.	Douillard JY, Kim E, Hirsh V, et al. Gefitinib (IRESSA) versus docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer pre-treated with platinum-based chemotherapy: a randomized, open-label Phase III study (INTEREST): PRS-02 [J]. J Thorac Oncol, 2007; 2(8): S305-S306.doi: 10.1097/01.JTO.0000283087.71346.19.
28.	Raymond E, Faivre S, Armand JP. Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy [J]. Drugs, 2000; 60 Suppl 1: 15-23.
29.	Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer) [J]. Lancet, 2005; 366(9496): 1527-1537.
30.	Oguey D, Marti U, Reichen J. Epidermal growth factor receptor in chronic bile duct obstructed rats: implications for maintenance of hepatocellular mass [J]. Eur J Cell Biol, 1992; 59(1): 187-195.
31.	Matsumoto K, Fujii H, Michalopoulos G, et al. Human biliary epithelial cells secrete and respond to cytokines and hepatocyte growth factors in vitro: interleukin-6, hepatocyte growth factor and epidermal growth factor promote DNA synthesis in vitro [J]. Hepatology, 1994; 20(2): 376-368.

1. Mok T, Wu YL, Zhang L. A small step towards personalized medicine for non-small cell lung cancer [J]. Discov Med, 2009; 8(43): 227-231.
2. Chu Q, Amano O, Kanda Y, et al. Tumor-specific Cytotoxicity and Type of Cell Death Induced by Gefitinib in Oral Squamous Cell Carcinoma Cell Lines [J]. Anticancer Res, 2009; 29(12): 5023-5031.
3. Yang CT, Hung JY, Lai CL, et al. Gefitinib as first-line therapy for advanced or metastatic non-small cell lung cancer patients in Southern Taiwan [J]. Kaohsiung J Med Sci, 2010; 26(1): 1-7.
4. Herbst RS, Fukuoka M, Baselga J. Gefitinib－a novel targeted approach to treating cancer [J]. Nat Rev Cancer, 2004; 4(12): 956-965.
5. Yoon JH, Gwak GY, Lee HS, et al. Enhanced epidermal growth factor receptor activation in human cholangiocarcinoma cells [J]. J Hepatol, 2004; 41(5): 808-814.
6. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase Ⅲ trial－INTACT 1 [J]. J Clin Oncol, 2004; 22(5): 777-784.
7. Hwang JH, Yoon YB, Kim YT, et al. Risk factors for recurrent cholangitis after initial hepatolithiasis treatment [J]. J Clin Gastroenterol, 2004; 38(4): 364-367.
8. Terada T, Nakanuma Y. Pathologic observations of intrahepatic peribiliary glands in 1 000 consecutive autopsy livers: Ⅳ. Hyperplasia of intramural and extramural glands [J]. Hum Pathol, 1992; 23(5): 483-490.
9. Terada T, Nakanuma Y. Innervation of intrahepatic bile ducts and peribiliary glands in normal human livers, extrahepatic biliary obstruction and hepatolithiasis. An immunohistochemical study [J]. J Hepatol, 1989; 9(2): 141-148.
10. Lu S, Yan L, Rao L, Xia T, et al. Down stream involvement of the bile duct in hepatolithiasis [J]. Chin Med J (Engl), 2002; 115(1): 62-64.
11. Uchiyama K, Kawai M, Ueno M, et al. Reducing residual and recurrent stones by hepatectomy for hepatolithiasis [J]. J Gastrointest Surg, 2007; 11(5): 626-630.
12. 货师鹏. 受体研究技术 [M]. 北京: 北京大学医学出版社, 2004: 275-277.
13. Schlessinger J. Cell signaling by receptor tyrosine kinases [J]. Cell, 2000; 103(2): 211-225.
14. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network [J]. Nat Rev Mol Cell Biol, 2001; 2(2): 127-137.
15. Hackel PO, Zwick E, Prenzel N, et al. Epidermal growth factor receptors: critical mediators of multiple receptor pathways [J]. Curr Opin Cell Biol, 1999; 11(2): 184-189.
16. Moghal N, Sternberg PW. Multiple positive and negative regulators of signaling by the EGF-receptor [J]. Curr Opin Cell Biol, 1999; 11(2): 190-196.
17. Ishii M, Vroman B, LaRusso NF. Morphologic demonstration of receptor-mediated endocytosis of epidermal growth factor by isolated bile duct epithelial cells [J]. Gastroenterology, 1990; 98(5 Pt 1): 1284-1291.
18. Van Winkle LS, Isaac JM, Plopper CG. Distribution of epidermal growth factor receptor and ligands during bronchiolar epithelial repair from naphthalene-induced Clara cell injury in the mouse [J]. Am J Pathol, 1997; 151(2): 443-459.
19. Giaccone G. HER1/EGFR-targeted agents: predicting the future for patients with unpredictable outcomes to therapy [J]. Ann Oncol, 2005; 16(4): 538-548.
20. Hamdi MM, Mutungi GM. Dihydrotestosterone activates the mitogen activated protein kinase pathway and modulates maximum isometric force in isolated intact mouse skeletal muscle fibres through the epidermal growth factor receptor [J]. J Physiol [Epub ahead of print]. PMID: 20008468. doi: 10.1113/jphysiol.2009.182162.
21. Kondratov KA, Chernorudskiy AL, Amosova AP, et al. Termination of tyrphostin AG1478 application results in different recovery of EGF receptor tyrosine residues 1 045 and 1 173 phosphorylation in A431 cells [J]. Cell Biol Int, 2010; 34(1): 81-87.
22. Donnellan F, Keating N, Geoghegan P, et al. JNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells [J]. Am J Physiol Gastrointest Liver Physiol, 2009 Oct 29[Epub ahead of print]. PMID: 19875701.
23. 正文, 朱明才, 汤为学, 等. 金雀异黄素与5-氟尿嘧啶对SGC-7901 细胞的抑制作用 [J]. 中国普外基础与临床杂志, 2008； 15（1）： 17-22.
24. 李龙, 岳红梅, 余勤. 表皮生长因子受体抑制剂与肺纤维化 [J]. 国外医学呼吸系统分册, 2005; 25(5): 345-348.
25. 龙怀聪, 王曾礼. 表皮生长因子受体拮抗剂对气道上皮细胞生长及修复的影响 [J]. 四川大学学报(医学版), 2003; 34(2): 254-256.
26. Fan ST, Choi TK, Lo CM, et al. Treatment of hepatolithiasis: improvement of result by a systematic approach [J]. Surgery, 1991; 109(4): 474-480.
27. Douillard JY, Kim E, Hirsh V, et al. Gefitinib (IRESSA) versus docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer pre-treated with platinum-based chemotherapy: a randomized, open-label Phase III study (INTEREST): PRS-02 [J]. J Thorac Oncol, 2007; 2(8): S305-S306.doi: 10.1097/01.JTO.0000283087.71346.19.
28. Raymond E, Faivre S, Armand JP. Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy [J]. Drugs, 2000; 60 Suppl 1: 15-23.
29. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer) [J]. Lancet, 2005; 366(9496): 1527-1537.
30. Oguey D, Marti U, Reichen J. Epidermal growth factor receptor in chronic bile duct obstructed rats: implications for maintenance of hepatocellular mass [J]. Eur J Cell Biol, 1992; 59(1): 187-195.
31. Matsumoto K, Fujii H, Michalopoulos G, et al. Human biliary epithelial cells secrete and respond to cytokines and hepatocyte growth factors in vitro: interleukin-6, hepatocyte growth factor and epidermal growth factor promote DNA synthesis in vitro [J]. Hepatology, 1994; 20(2): 376-368.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Effects of Gefitinib on Expression of Epidermal Growth Factor Receptor in Bile Duct Epithelial Cells and Its Significance

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