Expression of Keratinocyte Growth Factor and Cyclooxygenase-2 in Gastric Cancer and Its Correlation with Angiogenesis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

CHEN Zhendong ¹ , TAN Langping ¹ , WANG Yazhou ¹ , SUN Yansong ¹ , QIU Kun ²

1.The First Department of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002, Heilongjiang Province, China;;
2.The Second Department of Surgery, The Second People’s Hospital of Hainan Province, Wuzhishan 572200, Hainan Province, China;

Corresponding author：

Keywords：

Gastric cancer; Keratinocyte growth factor; Cyclooxygenase-2; Microvessel density; Angiogenesis

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ObjectiveTo investigate the expression of keratinocyte growth factor (KGF) and cyclooxygen-ase-2 (COX-2) protein and microvessel density (MVD), and to explore their function and mechanism in the multistep process of gastric cancer. MethodsThe expressions of KGF and COX-2 protein in 64 samples of gastric cancer and 30 cases of normal gastric mucosa tissues were detected by immunohistochemistry. The MVD was detected by staining the endothelial cells in microvessles using anti-CD34 antibody. ResultsThe positive rate of KGF and COX-2 protein expression in gastric cancer were 65.6% (42/64) and 79.7% (51/64), respectively, which was significantly higher than that in normal gastric mucosa tissues 〔(23.3%, 7/30), P=0.046; (13.3%, 4/30), P=0.008〕. The MVD of gastric cancer was 31.8±8.0, which was significantly higher than that of normal gastric mucosa tissues (14.3±6.1), P=0.000. The MVD in gastric cancer with coexpressive KGF and COX-2 protein was 35.9±5.7, which was significant higher than that with non-coexpressive KGF and COX-2 protein (25.7±7.0), P=0.000. Both the expression of KGF and COX-2 protein were related to the invasion of serosa, lymph node metastasis and TNM staging (P lt;0.05, P lt;0.01). The MVD of gastric cancer tissues was related to lymph node metastasis and TNM staging (P lt;0.05), but unrelated to patient’s age, gender, and differentiation of tumor
(P gt;0.05). The co-expression of KGF and COX-2 protein was frequently found in patients with deeper invasion of serosa, lymph node metastasis, and higher TNM staging (P lt;0.05), but which was not associated withpatient’sage, gender, and differentiation of tumor (P gt;0.05). The expression of KGF protein was positively correlated to the expression of COX-2 protein (r=0.610, P=0.000). There was positive correlation between MVD and the expression of KGF (r=0.675, P=0.000) and COX-2 protein (r=0.657, P=0.000) in gastric cancer, respectively. ConclusionKGF and COX-2 highly expressed by gastric cancer, which may be involved in the invasion and metastasis of gastric cancer by synergisticly promoting the angiogenesis.

Citation： CHEN Zhendong ,TAN Langping,WANG Yazhou,SUN Yansong,QIU Kun. Expression of Keratinocyte Growth Factor and Cyclooxygenase-2 in Gastric Cancer and Its Correlation with Angiogenesis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2011, 18(2): 177-182. doi: Copy

1.	宗宪磊, 蔡景龙, 姜笃银, 等. 角质细胞生长因子研究进展 [J]. 中国修复重建外科杂志, 2009, 23(2): 189190.
2.	Yamayoshi T, Nagayasu T, Matsumoto K, et al. Expression of keratinocyte growth factor/fibroblast growth factor7 and its receptor in human lung cancer: correlation with tumour proliferative activity and patient prognosis [J]. J Pathol, 2004, 204(1): 110118.
3.	Parrott JA, Kim G, Mosher R, et al. Expression and action of keratinocyte growth factor (KGF) in normal ovarian surface epithelium and ovarian cancer [J]. Mol Cell Endocrinol, 2000, 167(12): 7787.
4.	Crescioli C, Maggi M, Luconi M, et al. Vitamin D3 analogue inhibits keratinocyte growth factor signaling and induces apoptosis in human prostate cancer cells [J]. Prostate, 2002, 50(1): 1526.
5.	Planz B, Oltean H, Deix T, et al. Effect of keratinocyte growth factor and activin on cell growth in the human prostatic cancer cell line LNCaP [J]. World J Urol, 2004, 22(2): 140144.
6.	Watanabe M, Ishiwata T, Nishigai K, et al. Overexpression of keratinocyte growth factor in cancer cells and enterochromaffin cells in human colorectal cancer [J]. Pathol Int, 2000, 50(5): 363372.
7.	Kurban G, Ishiwata T, Kudo M, et al. Expression of keratinocyte growth factor receptor (KGFR/FGFR2 Ⅲb) in human uterine cervical cancer [J]. Oncol Rep, 2004, 11(5): 987991.
8.	Beer HD, Gassmann MG, Munz B, et al. Expression and function of keratinocyte growth factor and activin in skin morphogenesis and cutaneous wound repair [J]. J Investig Dermatol Symp Proc, 2000, 5(1): 3439.
9.	Gillis P, Savla U, Volpert OV, et al. Keratinocyte growth factor induces angiogenesis and protects endothelial barrier function [J]. J Cell Sci, 1999, 112(Pt 12): 20492057.
10.	Yashiro M, Nakazawa K, Tendo M, et al. Selective cyclooxygenase2 inhibitor downregulates the paracrine epithelialmesenchymal interactions of growth in scirrhous gastric carcinoma [J]. Int J Cancer, 2007, 120(3): 686693.
11.	Greene FL, Page DL, Fleming ID, et al. 毛伟征, 苏东明, 李雪萍, 等译. AJCC癌症分期手册 [M]. 第6版. 沈阳: 辽宁科学技术出版社， 2005: 99102.
12.	王秀梅, 黎莉, 郝静, 等. KGF在乳腺癌的表达与临床意义 [J]. 中国现代普通外科进展, 2006, 9(1): 3739.
13.	汲克强, 张稷. COX2在肺鳞癌及腺癌组织中的表达及其与MVD的相关性 [J]. 临床肺科杂志, 2008, 13(9): 11651166.
14.	Weidner N. Tumoural vascularity as a prognostic factor in cancer patients: the evidence continues to grow [J]. J Pathol, 1998, 184(2): 119122.
15.	Cho K, Ishiwata T, Uchida E, et al. Enhanced expression of keratinocyte growth factor and its receptor correlates with venous invasion in pancreatic cancer [J]. Am J Pathol, 2007, 170(6): 19641974.
16.	Narita K, Fujii T, Ishiwata T, et al. Keratinocyte growth factor induces vascular endothelial growth factorA expression in colorectal cancer cells [J]. Int J Oncol, 2009, 34(2): 355360.
17.	Fujiwaki R, Iida K, Kanasaki H, et al. Cyclooxygenase2 expression in endometrial cancer: corrrelation with microvessel count and expression of vascular endothelial growth factor and thymidine phosphorylase [J]. Hum Pathol, 2002, 33(2): 213219.
18.	Nakazawa K, Yashiro M, Hirakawa K. Keratinocyte growth factor produced by gastric fibroblasts specifically stimulates proliferation of cancer cells from scirrhous gastric carcinoma [J]. Cancer Res, 2003, 63(24): 88488852.
19.	Yoshino M, Ishiwata T, Watanabe M, et al. Expression and roles of keratinocyte growth factor and its receptor in esophageal cancer cells [J]. Int J Oncol, 2007, 31(4): 721728.
20.	Huang YW, Wang LS, Chang HL, et al. Effect of keratinocyte growth factor on cell viability in primary cultured human prostate cancer stromal cells [J]. J Steroid Biochem Mol Biol, 2006, 100(13): 2433.
21.	Rubin JS, Osada H, Finch PW, et al. Purification and characterization of a newly identified growth factor specific for epithelial cells [J]. Proc Natl Acad Sci U S A, 1989, 86(3): 802806.
22.	GustafsonSvrd C, Lilja I, Hallbk O, et al. Cyclooxygenase1 and cyclooxygenase2 gene expression in human colorectal adenocarcinomas and in azoxymethane induced colonic tumours in rats [J]. Gut, 1996, 38(1): 7984.
23.	Uefuji K, Ichikura T, Mochizuki H, et al. Expression cyclooxygenase2 in human gastric adenomas and carcinomas [J]. J Surg Oncol, 2001, 76(1): 2630.
24.	李玉民, 薛群基, 周彦明, 等. 胃癌组织中环氧合酶2的表达及其意义 [J]. 中国普外基础与临床杂志, 2003, 10(2): 137139.
25.	Leung WK, To KF, Ng YP, et al. Association between cyclooxygenase2 overexpression and missense p53 mutations in gastric cancer [J]. Br J Cancer, 2001, 84(3): 335339.
26.	Joo YE, Oh WT, Rew JS, et al. Cyclooxygenase2 expression is associated with welldifferentiated and intestinaltype pathways in gastric carcinogenesis [J]. Digestion, 2002, 66(4): 222229.
27.	Shono T, Tofilon PJ, Bruner JM, et al. Cyclooxygenase2 expression in human gliomas: prognostic significance and molecular correlations [J]. Cancer Res, 2001, 61(11): 43754381.
28.	王广义, 王旭. 人胃癌VEGF和NOS的表达与肿瘤血管生成的关系 [J]. 中国普外基础与临床杂志, 2004, 11(1): 5557.
29.	Gallo O, Masini E, Bianchi B, et al. Prognostic significance of cyclooxygenase2 pathway and angiogenesis in head and neck squamous cell carcinoma [J]. Hum Pathol, 2002, 33(7): 708714.
30.	Ghosh AK, Hirasawa N, Niki H, et al. Cyclooxygenase2mediated angiogenesis in carrageenininduced granulation tissue in rats [J]. J Pharmacol Exp Ther, 2000, 295(2): 802809.
31.	Liu XH, Kirschenbaum A, Yao S, et al. Upregulation of vascular endothelial growth factor by cobalt chloridesimulated hypoxia is mediated by persistent induction of cyclooxygenase2 in a metastatic human prostate cancer cell line [J]. Clin Exp Metastasis, 1999, 17(8): 687694.
32.	Cantu De Leon D, LopezGraniel C, Frias Mendivil M, et al. Significance of microvascular density (MVD) in cervical cancer recurrence [J]. Int J Gynecol Cancer, 2003, 13(6): 856862.
33.	Ludovini V, Sidoni A, Pistola L, et al. Evaluation of the prognostic role of vascular endothelial growth factor and microvessel density in stages Ⅰ and Ⅱ breast cancer patients [J]. Breast Cancer Res Treat, 2003, 81(2): 159168.
34.	Folkman J. What is the evidence that tumors are angiogenesis dependent? [J]. J Natl Cancer Inst, 1990, 82(1): 46.
35.	Uzan B, Figeac F, Portha B, et al. Mechanisms of KGF mediated signaling in pancreatic duct cell proliferation and differentiation [J]. PLoS One, 2009, 4(3): e4734.
36.	Pai R, Szabo IL, Soreghan BA, et al. PGE2 stimulates VEGF expression in endothelial cells via ERK2/JNK1 signaling pathways [J]. Biochem Biophys Res Commun, 2001, 286(5): 923928.

1. 宗宪磊, 蔡景龙, 姜笃银, 等. 角质细胞生长因子研究进展 [J]. 中国修复重建外科杂志, 2009, 23(2): 189190.
2. Yamayoshi T, Nagayasu T, Matsumoto K, et al. Expression of keratinocyte growth factor/fibroblast growth factor7 and its receptor in human lung cancer: correlation with tumour proliferative activity and patient prognosis [J]. J Pathol, 2004, 204(1): 110118.
3. Parrott JA, Kim G, Mosher R, et al. Expression and action of keratinocyte growth factor (KGF) in normal ovarian surface epithelium and ovarian cancer [J]. Mol Cell Endocrinol, 2000, 167(12): 7787.
4. Crescioli C, Maggi M, Luconi M, et al. Vitamin D3 analogue inhibits keratinocyte growth factor signaling and induces apoptosis in human prostate cancer cells [J]. Prostate, 2002, 50(1): 1526.
5. Planz B, Oltean H, Deix T, et al. Effect of keratinocyte growth factor and activin on cell growth in the human prostatic cancer cell line LNCaP [J]. World J Urol, 2004, 22(2): 140144.
6. Watanabe M, Ishiwata T, Nishigai K, et al. Overexpression of keratinocyte growth factor in cancer cells and enterochromaffin cells in human colorectal cancer [J]. Pathol Int, 2000, 50(5): 363372.
7. Kurban G, Ishiwata T, Kudo M, et al. Expression of keratinocyte growth factor receptor (KGFR/FGFR2 Ⅲb) in human uterine cervical cancer [J]. Oncol Rep, 2004, 11(5): 987991.
8. Beer HD, Gassmann MG, Munz B, et al. Expression and function of keratinocyte growth factor and activin in skin morphogenesis and cutaneous wound repair [J]. J Investig Dermatol Symp Proc, 2000, 5(1): 3439.
9. Gillis P, Savla U, Volpert OV, et al. Keratinocyte growth factor induces angiogenesis and protects endothelial barrier function [J]. J Cell Sci, 1999, 112(Pt 12): 20492057.
10. Yashiro M, Nakazawa K, Tendo M, et al. Selective cyclooxygenase2 inhibitor downregulates the paracrine epithelialmesenchymal interactions of growth in scirrhous gastric carcinoma [J]. Int J Cancer, 2007, 120(3): 686693.
11. Greene FL, Page DL, Fleming ID, et al. 毛伟征, 苏东明, 李雪萍, 等译. AJCC癌症分期手册 [M]. 第6版. 沈阳: 辽宁科学技术出版社， 2005: 99102.
12. 王秀梅, 黎莉, 郝静, 等. KGF在乳腺癌的表达与临床意义 [J]. 中国现代普通外科进展, 2006, 9(1): 3739.
13. 汲克强, 张稷. COX2在肺鳞癌及腺癌组织中的表达及其与MVD的相关性 [J]. 临床肺科杂志, 2008, 13(9): 11651166.
14. Weidner N. Tumoural vascularity as a prognostic factor in cancer patients: the evidence continues to grow [J]. J Pathol, 1998, 184(2): 119122.
15. Cho K, Ishiwata T, Uchida E, et al. Enhanced expression of keratinocyte growth factor and its receptor correlates with venous invasion in pancreatic cancer [J]. Am J Pathol, 2007, 170(6): 19641974.
16. Narita K, Fujii T, Ishiwata T, et al. Keratinocyte growth factor induces vascular endothelial growth factorA expression in colorectal cancer cells [J]. Int J Oncol, 2009, 34(2): 355360.
17. Fujiwaki R, Iida K, Kanasaki H, et al. Cyclooxygenase2 expression in endometrial cancer: corrrelation with microvessel count and expression of vascular endothelial growth factor and thymidine phosphorylase [J]. Hum Pathol, 2002, 33(2): 213219.
18. Nakazawa K, Yashiro M, Hirakawa K. Keratinocyte growth factor produced by gastric fibroblasts specifically stimulates proliferation of cancer cells from scirrhous gastric carcinoma [J]. Cancer Res, 2003, 63(24): 88488852.
19. Yoshino M, Ishiwata T, Watanabe M, et al. Expression and roles of keratinocyte growth factor and its receptor in esophageal cancer cells [J]. Int J Oncol, 2007, 31(4): 721728.
20. Huang YW, Wang LS, Chang HL, et al. Effect of keratinocyte growth factor on cell viability in primary cultured human prostate cancer stromal cells [J]. J Steroid Biochem Mol Biol, 2006, 100(13): 2433.
21. Rubin JS, Osada H, Finch PW, et al. Purification and characterization of a newly identified growth factor specific for epithelial cells [J]. Proc Natl Acad Sci U S A, 1989, 86(3): 802806.
22. GustafsonSvrd C, Lilja I, Hallbk O, et al. Cyclooxygenase1 and cyclooxygenase2 gene expression in human colorectal adenocarcinomas and in azoxymethane induced colonic tumours in rats [J]. Gut, 1996, 38(1): 7984.
23. Uefuji K, Ichikura T, Mochizuki H, et al. Expression cyclooxygenase2 in human gastric adenomas and carcinomas [J]. J Surg Oncol, 2001, 76(1): 2630.
24. 李玉民, 薛群基, 周彦明, 等. 胃癌组织中环氧合酶2的表达及其意义 [J]. 中国普外基础与临床杂志, 2003, 10(2): 137139.
25. Leung WK, To KF, Ng YP, et al. Association between cyclooxygenase2 overexpression and missense p53 mutations in gastric cancer [J]. Br J Cancer, 2001, 84(3): 335339.
26. Joo YE, Oh WT, Rew JS, et al. Cyclooxygenase2 expression is associated with welldifferentiated and intestinaltype pathways in gastric carcinogenesis [J]. Digestion, 2002, 66(4): 222229.
27. Shono T, Tofilon PJ, Bruner JM, et al. Cyclooxygenase2 expression in human gliomas: prognostic significance and molecular correlations [J]. Cancer Res, 2001, 61(11): 43754381.
28. 王广义, 王旭. 人胃癌VEGF和NOS的表达与肿瘤血管生成的关系 [J]. 中国普外基础与临床杂志, 2004, 11(1): 5557.
29. Gallo O, Masini E, Bianchi B, et al. Prognostic significance of cyclooxygenase2 pathway and angiogenesis in head and neck squamous cell carcinoma [J]. Hum Pathol, 2002, 33(7): 708714.
30. Ghosh AK, Hirasawa N, Niki H, et al. Cyclooxygenase2mediated angiogenesis in carrageenininduced granulation tissue in rats [J]. J Pharmacol Exp Ther, 2000, 295(2): 802809.
31. Liu XH, Kirschenbaum A, Yao S, et al. Upregulation of vascular endothelial growth factor by cobalt chloridesimulated hypoxia is mediated by persistent induction of cyclooxygenase2 in a metastatic human prostate cancer cell line [J]. Clin Exp Metastasis, 1999, 17(8): 687694.
32. Cantu De Leon D, LopezGraniel C, Frias Mendivil M, et al. Significance of microvascular density (MVD) in cervical cancer recurrence [J]. Int J Gynecol Cancer, 2003, 13(6): 856862.
33. Ludovini V, Sidoni A, Pistola L, et al. Evaluation of the prognostic role of vascular endothelial growth factor and microvessel density in stages Ⅰ and Ⅱ breast cancer patients [J]. Breast Cancer Res Treat, 2003, 81(2): 159168.
34. Folkman J. What is the evidence that tumors are angiogenesis dependent? [J]. J Natl Cancer Inst, 1990, 82(1): 46.
35. Uzan B, Figeac F, Portha B, et al. Mechanisms of KGF mediated signaling in pancreatic duct cell proliferation and differentiation [J]. PLoS One, 2009, 4(3): e4734.
36. Pai R, Szabo IL, Soreghan BA, et al. PGE2 stimulates VEGF expression in endothelial cells via ERK2/JNK1 signaling pathways [J]. Biochem Biophys Res Commun, 2001, 286(5): 923928.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Expression of Keratinocyte Growth Factor and Cyclooxygenase-2 in Gastric Cancer and Its Correlation with Angiogenesis

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