Cyclooxygenase-2 Expression Is Related to the Epithelial-to-Mesenchymal Transition in Human Colon Cancers

다국어 초록 (Multilingual Abstract)

Purpose: Down-regulation of E-cadherin is a hallmark of the epithelial-to-mesenchymal transition (EMT). EMT
progression in cancer cells is associated with the loss of certain epithelial markers and the acquisition of a
mesenchymal phenotype, as well as migratory activities. Cyclooxygenase-2 (COX-2) expression is associated with
tumor invasion and metastasis in colon cancer. This study investigated the relationship between E-cadherin and
COX-2 in colon cancer cells and human colon tumors. Materials and Methods: Colon cancer cell lines and
immunohistochemistry were used. Results: E-cadherin expression was inversely related to the expressions of
COX-2 and Snail in colon cancer cells. Ectopic expression of COX-2 or Snail reduced E-cadherin and induced a
scattered, flattened phenotype with few intercellular contacts in colon cancer cells. Treatment of cancer cells with
phorbol 12-myristate 13-acetate increased the expressions of COX-2 and Snail, decreased 15-hydroxyprostaglandin
dehydrogenase expression, and increased the cells’ motility. In addition, exposure to prostaglandin E2 increased
Snail expression and cell motility, and decreased E-cadherin expression. Membranous E-cadherin expression was
lower in adenomas and cancers than in the adjacent, non-neoplastic epithelium. In contrast, the expressions of Snail
and COX-2 were higher in cancers than in normal tissues and adenomas. The expressions of COX-2 and Snail
increased in areas with abnormal E-cadherin expression. Moreover, COX-2 expression was related to higher tumor
stages and was significantly higher in nodal metastatic lesions than primary cancers. Conclusion: This study
suggests that COX-2 may have a role in tumor metastasis via EMT.

다국어 초록 (Multilingual Abstract)

Purpose: Down-regulation of E-cadherin is a hallmark of the epithelial-to-mesenchymal transition (EMT). EMT
progression in cancer cells is associated with the loss of certain epithelial markers and the acquisition of a
mesenchymal phenotype, as well as migratory activities. Cyclooxygenase-2 (COX-2) expression is associated with
tumor invasion and metastasis in colon cancer. This study investigated the relationship between E-cadherin and
COX-2 in colon cancer cells and human colon tumors. Materials and Methods: Colon cancer cell lines and
immunohistochemistry were used. Results: E-cadherin expression was inversely related to the expressions of
COX-2 and Snail in colon cancer cells. Ectopic expression of COX-2 or Snail reduced E-cadherin and induced a
scattered, flattened phenotype with few intercellular contacts in colon cancer cells. Treatment of cancer cells with
phorbol 12-myristate 13-acetate increased the expressions of COX-2 and Snail, decreased 15-hydroxyprostaglandin
dehydrogenase expression, and increased the cells’ motility. In addition, exposure to prostaglandin E2 increased
Snail expression and cell motility, and decreased E-cadherin expression. Membranous E-cadherin expression was
lower in adenomas and cancers than in the adjacent, non-neoplastic epithelium. In contrast, the expressions of Snail
and COX-2 were higher in cancers than in normal tissues and adenomas. The expressions of COX-2 and Snail
increased in areas with abnormal E-cadherin expression. Moreover, COX-2 expression was related to higher tumor
stages and was significantly higher in nodal metastatic lesions than primary cancers. Conclusion: This study
suggests that COX-2 may have a role in tumor metastasis via EMT.

참고문헌 (Reference)

1 Peinado H, "Transcriptional regulation of cadherins during development and carcinogenesis" 48 : 365-375, 2004

2 Guarino M, "The role of epithelial-mesenchymal transition in cancer pathology" 39 : 305-318, 2007

3 Barrallo-Gimeno A, "The Snail genes as inducers of cell movement and survival: implications in development and cancer" 132 : 3151-3161, 2005

4 Chang YW, "RhoA mediates cyclooxygenase-2 signaling to disrupt the formation of adherens junctions and increase cell motility" 66 : 11700-11708, 2006

5 Mann JR, "Repression of prostaglandin dehydrogenase by epidermal growth factor and snail increases prostaglandin E2 and promotes cancer progression" 66 : 6649-6656, 2006

6 Barberà MJ, "Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells" 23 : 7345-7354, 2004

7 Wang D, "Prostaglandins and cancer" 55 : 115-122, 2006

8 Zhang H, "Overexpression of cyclooxygenase-2 correlates with advanced stages of colorectal cancer" 97 : 1037-1041, 2002

9 Ohta T, "Increased protein expression of both inducible nitric oxide synthase and cyclooxygenase-2 in human colon cancers" 239 : 246-253, 2006

10 Hirohashi S, "Inactivation of the E-cadherin-mediated cell adhesion system in human cancer" 153 : 333-339, 1998

11 Thiery JP, "Epithelial-mesenchymal transitions in tumour progression" 2 : 442-454, 2002

12 Noda M, "Effects of etodolac, a selective cyclooxygenase- 2 inhibitor, on the expression of E-cadherin-catenin complexes in gastrointestinal cell lines" 37 : 896-904, 2002

13 Jungck M, "E-cadherin expression is homogeneously reduced in adenoma from patients with familial adenomatous polyposis: an immunohistochemical study of E-cadherin, betacatenin and cyclooxygenase-2 expression" 19 : 438-445, 2004

14 Dohadwala M, "Cyclooxygenase-2-dependent regulation of E-cadherin: prostaglandin E (2) induces transcriptional repressors ZEB1 and snail in non-small cell lung cancer" 66 : 5338-5345, 2006

15 Vleminckx K, "Cadherins and tissue formation: integrating adhesion and signaling" 21 : 211-220, 1999

16 Brown JR, "COX-2: a molecular target for colorectal cancer prevention" 23 : 2840-2855, 2005

17 Nosho K, "Association of Ets-related transcriptional factor E1AF expression with overexpression of matrix metalloproteinases, COX-2 and iNOS in the early stage of colorectal carcinogenesis" 26 : 892-899, 2005

18 Bellovin DI, "Altered localization of p120 catenin during epithelial to mesenchymal transition of colon carcinoma is prognostic for aggressive disease" 65 : 10938-10945, 2005

19 Tsujii M, "Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2" 83 : 493-501, 1995