비소세포폐암에서 COX-2, MMP-9와 돌연변이형p53의 발현이 생존에 대한 예후 분석

신종욱 ( Jong Wook Shin ),최재호 ( Jae Ho Choi ),박인원 ( In Won Park ),유재형 ( Jae Hyung Yoo ) 대한결핵 및 호흡기학회 2007 Tuberculosis and Respiratory Diseases Vol.63 No.1

연구배경: 폐암의 병인에 기여하거나 예후를 결정하는 인자에 대해서는 매우 다양한 인자와 다양한 상호 관계로 인하여 특히 유전자의 역할에 대해서는 결정적으로 알려진 것이 없어 앞으로 더 많은 연구가 필요한 실정이다. 이에 따라 본 연구에서는 COX-2, MMP-9, p53가 비소세포폐암에서 어떻게 발현되는지 세포면역학적으로 알아보고 임상 특성과 예후와 상관관계를 알아보고자 하였다. 대상 및 방법: 91명의 비소세포폐암을 대상으로 하여 후향적으로 임상특성을 고찰하고 COX-2, MMP- 9, p53의 유전자 표현을 세포면역학적 방법을 통하여 검사하였다. 임상특성과 유전자 표현 패턴의 상관관계와 생존에 대한 예후인자로서의 역할에 대하여 조사하였다. 결과: 1) 편평상피세포암에서는 흡연자과 남자가 우세한 비율을 차지하였으며 남자에서 흡연의 비율이 유의하게 높았다. 2) 전체 대상 환자에서 생존에 영향을 미치는 결정적인 인자는 근치적 절제술의 시행여부와 병기로 나타났다. 3) COX-2의 발현은 편평상피세포암 보다 선암에서 더 유의하게 높게 발현되었다. 4) COX-2, MMP-9, p53의 발현이 모두 되지 않는 비율은 선암에 비해 편평상피세포암에서 더 흔하게 관찰되었다. 5) p53돌연변이가 있으면서 COX-2와 MMP-9은 발현이 되지 않는 비소세포폐암환자의 생존기간이 다른 발현 양상을 보이는 경우에서의 생존기간보다 더 연장되어 보였다(생존기간의 중앙값; 165.6주). 6) COX-2의 발현과 MMP-9의 발현 사이에는 유의한 상관관계가 있었다. 7) 폐암을 근치적으로 절제한 환자의 경우에 COX-2의 발현은 유의한 예후인자였다. MMP-9는 근치적 절제술을 받지 못한 환자군에서 유의한 예후인자로 작용하였다. 결론: COX-2와 MMP-9의 발현은 비소세포폐암 환자 일부에서 병의 진행에 관여하거나 예후에 영향을 줄 수 있을 것으로 기대된다. Background: In pathogenesis and prognosis of lung cancer, significance of enormous types of genetic expression were very compounding and undetermined. We performed this study to search association between clinical characteristics and expression of COX-2, MMP-9 and p53 in non-small cell lung cancer. Methods: Ninety-one patients with adenocarcinoma or squamous cell carcinoma were enrolled. We had searched clinical data retrospectively and performed immunohistochemical staining for COX-2, MMP-9 and p53. We had analyzed significance of these three genes in clinical features and prognosis for survival. Results: 1) In squamous cell carcinoma, male was predominant and was significantly correlated with smoking. 2) Major prognostic determinants for overall survival were curative resection. 3) Expression of COX-2 was more frequent in adenocarcinoma than in squamous cell carcinoma. 4) Negative staining of COX-2, MMP-9 and p53 was more frequent in squamous cell carcinoma than adenocarcinoma. 5) Survival duration was longer in the group with positive expression of p53 and negative for COX-2 and MMP-9 (median duration of survival = 165.6 weeks) than groups with the other expressional patterns. 6) Significant correlation was found between expression of MMP-9 and COX-2. In squamous cell carcinoma, expression of MMP-9, COX-2 and mutant p53 were mutually correlated. 7) COX-2 expression was significant prognostic factor for survival in resected cancer group. In unresected inoperable non-small cell lung cancer group, MMP-9 was statistically significant prognostic factor for overall survival. Conclusion: COX-2 and MMP-9 might have some roles for progression or prognosis in some selected patients with non-small cell lung cancer. COX-2 and MMP-9 may have some roles for disease progression or prognosis in selected patients with NSCLC. (Tuberc Respir Dis 2007; 63: 31-41)

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

장태정,전규하,정기훈 연세대학교의과대학 2009 Yonsei medical journal Vol.50 No.6

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. 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.

상피성 난소암에서의 COX-2의 발현과 예후

김원규 고신대학교의과대학 2006 고신대학교 의과대학 학술지 Vol.21 No.2

Background and Purpose : The prognostic factors for predicting the clinical progress in ovarian cancer have not been clear up to date. Among the several prognostic factors for ovarian cancer suggested recently, Cyclooxygenase-2(COX-2) has drawn the most attention. This study tested an hypothesis that expression of COX-2 is the indication of carcinogenesis. COX is an enzyme responsible for the production of prostaglandins from arachidonic acid. COX-2 is induced by cytokines, growth factors, and tumor promotors and it is an early response gene in inflammation, and there is a growing evidence that COX-2 expression is important in carcinogenesis. It is thought that COX-2 may regulate cell proliferation, mitosis, cell adhesion, apoptosis, immune surveillance and angiogenesis during carcinogenesis. This study was conducted to examine the relation of COX-2 to epithelial ovarian cancer and to examine its effect on the survival rate, thus proving its usefulness as prognostic factor. Methods : Thirty-one patients with epithelial ovarian cancer who went under surgery at Kosin University Hospital from 1995 (January) to 2001 (December) participated in this study. Using the immunohistochemistry method on the tissue samples, COX-2 levels in the patients were compared with 12 other patients with benign ovarian tumor. Univariate analysis was tested with Chi-square and survival rate was tested using the Kaplan-Meier and Log-rank methods. And for the indicators that revealed a significant difference, cox-proportional hazard model was additionally used for the multivariate analysis. Results : Five year survival rate for the 31 patients of epithelial ovarian cancer was 58.4%. Both histologic type (p<0.05) and the FIGO stage (p<0.05) were found to have a statistically significant relationship with the survival rate. Regarding epithelial ovarian tumor, there was a significantly higher level of COX-2 (p<0.05) in the patients with cancer compared to those with benign tumor. Age as the prognostic factor was positively correlated with COX-2. The positive group of COX-2 showed significantly lower survival rate than negative group (respectively, p<0.05). In the multivariate analysis only FIGO stage showed statistically significant relationship. Conclusion : In this study COX-2 couldn't be an independent prognostic factor for ovarian cancer due to multivariate analysis, but we can suggest that COX-2 might play a role in ovarian carcinogenesis.

Quantitative analysis of COX-2 promoter methylation in gastric carcinoma

Ho Goon Kim,Seong Yeob Ryu,Kyung Hwa Lee,Jae Hyuk Lee,Dong Yi Kim 대한외과학회 2018 Annals of Surgical Treatment and Research(ASRT) Vol.95 No.2

Purpose: To determine the occurrence of COX-2 methylation in gastric carcinoma (GC), the status and level of CpG methylation in the promoter region of cyclooxygenase-2 (COX-2) were analyzed in early and advanced GCs, as well as in normal gastric tissues. Methods: The extent of promoter methylation of the COX-2 gene was assessed quantitatively using pyrosequencing in 60 early and 60 advanced GCs samples harvested upon gastrectomy, and 40 normal gastric mucosa samples from patients with benign gastric diseases as controls. Results: The methylation frequency for the COX-2 gene was significantly higher in early than in advanced GCs (40.0% vs. 20.0%, P < 0.05). A significant difference was found in COX-2 methylation between GCs and normal gastric tissues (30.0% vs. 10.0%, by PS; P < 0.05). COX-2 gene methylation was significantly associated with the depth of invasion (P = 0.003), lymph node metastasis (P = 0.009), distant metastasis (P = 0.036), and TNM staging (P = 0.007). The overall survival of patients with COX-2 methylation was significantly lower than that of patients without COX-2 methylation (P = 0.005). Conclusion: These results demonstrated that COX-2 promoter methylation was significantly higher in tumor tissues, and was an early event for GC, thus, COX-2 gene methylation may be important in the initial development of gastric carcinogenesis. Thus, GCs with methylation in COX-2 may not be good candidates for treatment with COX-2 inhibitors. Furthermore, COX-2 methylation could be a significant prognostic factor predicting a favorable effect on GC patient outcome when downregulated.

Feedback Control of Cyclooxygenase-2 Expression by Prostaglandin E2 in Rheumatoid Synoviocytes

Min, So-Youn,Jung, Young Ok,Do, Ju-Ho,Kim, So-Yang,Kim, Jeong-Pyo,Cho, Chul-Soo,Kim, Wan-Uk The Korean Association of Immunobiologists 2003 Immune Network Vol.3 No.3

Objective: The role of prostaglandin $E_2$ (PGE2) in the etiopathogenesis of immune and inflammatory diseases has become the subject of recent debate. To determine the role of PGE2 in rheumatoid arthritis (RA), we tested the effect of exogenous PGE2 on the production of cyclooxygenase-2 (COX-2) by rheumatoid synoviocytes. Methods: Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of RA patients, and cultured in the presence of PGE2. The COX-2 mRNA and protein expression levels were determined by RT-PCR and Western blot analysis, respectively. The PGE2 receptor subtypes in the FLS were analyzed by RT-PCR. Electrophoretic mobility shift assay (EMSA) was used to measure the NF-${\kappa}B$ binding activity for COX-2 transcription. The in vivoeffect of PGE2 on the development of arthritis was also tested in collagen induced arthritis (CIA) animals. Results: PGE2 ($10^{-11}$ to $10^{-5}M$) dose-dependently inhibited the expression of COX-2 mRNA and the COX-2 protein stimulated with IL-$1{\beta}$, but not COX-1 mRNA. NS-398, a selective COX-2 inhibitor, displayed an additive effect on PGE2-induced COX-2 downregulation. The FLS predominantly expressed the PGE2 receptor (EP) 2 and EP4, which mediated the COX-2 suppression by PGE2. Treatment with anti-IL-10 monoclonal antibodies partially reversed the PGE2-induced suppression of COX-2 mRNA, suggesting that IL-10 may be involved in modulating COX-2 by PGE2. Experiments using an inducer and an inhibitor of cyclic AMP (cAMP) suggest that cAMP is the major intracellular signal that mediates the regulatory effect of PGE2 on COX-2 expression. EMSA revealed that PGE2 inhibited the binding of NF-${\kappa}B$ in the COX-2 promoter via a cAMP dependent pathway. In addition, a subcutaneous injection of PGE2 twice daily for 2 weeks significantly reduced the incidence and severity of CIA as well as the production of IgG antibodies to type II collagen. Conclusion: Our data suggest that overproduced PGE2 in the RA joints may function as an autocrine regulator of its own synthesis by inhibiting COX-2 production and may, in part, play an anti-inflammatory role in the arthritic joints.

정상 자궁내막, 자궁내막 증식증, 자궁 내막암에서의 cyclooxygenase-2,p53 발현율 비교 연구

유상욱,이낙우,이규완,김옥경,송재윤,홍순철 대한부인종양학회 2006 Journal of Gynecologic Oncology Vol.16 No.3

Objective: The purpose of this study is to compare the expression rate of cyclooxygenase-2(COX-2), p53 in endometrial hyperplasia ,endometrial cancer and normal endometrium and to correlate COX-2 with the clinicopathological factors and p53 in endometrial cancer. Materials and methods: Immunohistochemical stain of COX-2, p53 was performed on samples from a series of 19 cases of normal proliferative endometrium, 20 cases of complex endometrial hyperplasia and 19 cases of endometrial cancer. And then we analyzed the expression of COX-2 correlated the findings with clinicopathological factors and p53. Expression of COX-2 was scored according to the proportion of positive-staining cells: negative, no staining; 1+, <10%; 2+, 10-50%; 3+, >50. For p53 overexpression, when there were at least 10% of tumor cells stained , it was considered as positive. Results: Overexpression of COX-2(≥2+) was seen in 5(26.3%) of the endometrial cancers, 6(30%) of the complex endometrial hyperplasia, and 4(21.1%) of the normal endometria. The expression rates of COX-2 in endometrial cancer, hyperplasia and normal endometrium were not different statistically significant(p=0.93). COX-2 was not correlated with clinicopathological factors but correlated with p53 significantly (p=0.021). Conclusion: In this study, the immunohistochemical analysis showed no difference statistically in COX-2 expression between endometrial cancer and hyperplasia compared to normal endometria. COX-2 was significantly correlated with p53. This finding may represent that tumor suppressor p53 upregulates COX-2 expression 목적: Cyclooxygenase-2(COX-2) 과발현이 대장암, 자궁 경부암, 유방암, 방광암등 여러 암에서 보고되고 있고, 최근에는 자궁내막암에서 COX-2발현 양상에 관한 연구가 이루어지고 있다. 여러 보고에서 COX-2와 p53의 상관관계와 기전에 대한 연구가 이루어지고 있다. 이에 본 연구에서는 자궁내막증식증과 자궁내막암에서의 COX-2 발현율을 정상 자궁내막과 비교하고 임상예후인자로서의 가능성을 확인하며 COX-2 발현이 p53과 관련성이 있는지에 관하여 살펴보았다. 연구 방법: 2000년 1월부터 2005년 10월까지 고려대학교 안암병원 산부인과학 교실에서 자궁 내막 생검 또는 자궁 적출술을 통해 외과적으로 절제된 정상 증식기 자궁 내막 19예, 복합성 자궁 내막 증식증(complex endometrial hyperplasia) 20예, 자궁 내막암으로 확진된 19예 등 58예를 대상으로 하였다. 자궁내막 조직에 COX-2, p53으로 면역 조직 화학 염색을 시행하여 그 결과를 COX-2는 염색 강도에 따라 음성, 1+,2+3+로 판독하였고, p53은 음성과 양성 두군으로 판독하였다. 세 군에서의 COX-2, p53염색 결과를 비교하였고, COX-2와 p53의 관계를 알아보았다. 결과: 세 군에서의 COX-2 양성율을 비교한 결과 정상 자궁 내막, 복합성 자궁내막 증식증, 자궁내막암 세군 간에 유의한 차이는 보이지 않았다. COX-2 강양성(2+이상)으로 판독한 결과 정상 자궁내막 4/19예(21.1%), 복합성 자궁내막 증식증 6/20예(30%), 자궁 내막암 5/19예(26.3%)로 정상 자궁내막에 비해 복합성 자궁내막증식증과 자궁내막암에서 COX-2 강양성율이 높았으나 통계학적으로 유의하지는 않았다(p=0.930). COX-2면역조직 화학 염색 결과와 p53 면역 조직 화학 염색 결과와의 관련성을 비교한 결과 p53에서 양성을 보인 10/10예(100%)에서 COX-2 양성을 보였으며(p=0.021), p53 양성과 COX-2 강양성(2+이상) 사이의 상관관계도 유의한 결과를 나타났다(p=0.013) 결론: 결론적으로, 복합성 자궁내막증식증, 자궁내막암에서 정상 자궁 내막에서의 COX-2 발현율은 통계학적으로 유의한 차이를 보이지 않았고 자궁내막암의 임상적 예후 인자와도 관련성을 입증하지는 못하였으나 COX-2 발현은 p53 발현과 유의한 상관관계를 보였다. 이는 아마도 p53이 COX-2발현을 증가시킨 결과로 판단된다.

비소세포 폐암에서 COX-2, MMP-9, p53 및 VEGF 발현에 대한 면역조직화학적 연구 : 편평세포암종과 선암종을 대상으로

하경원 외 중앙대학교 의과대학 의학연구소 2007 中央醫大誌 Vol.32 No.3

Purpose: This study was performed to investigate immunohistochemical expression of COX-2, MMP-9 and p53 using surgical specimens of 97 non-small-cell lung cancer cases and to evaluate the relationship between the expression of each molecule and clinicopathologic factors or prognosis. Methods: The following formalin-fixed paraffin embedded surgical specimens were immunohistochemically stained by avidin-biotin complex method for COX-2, MMP-9 and p53; 60 cases of primary squamous cell carcinoma and 37 cases of primary adenocarcinoma of the lung. Results: COX-2 expression of adenocarcinoma is statistically higher than that of squamous cell carcinoma (p<0.01). However, MMP-9, p53 and VEGF expression is not significantly associated with the histologic type of cancer. COX-2 expression was significantly associated with the clinical staging (p<0.05), whereas MMP-9, p53 and VEGF expression were not. Synchronous expression of each molecules (COX-2 + MMP-9 + p53 + VEGF, COX-2 + MMP-9 +p53, COX-2 + MMP-9 + VEGF, COX-2 + p53 + VEGF, COX-2 + MMP-9, COX-2 + p53, MMP-9 + p53, COX-2 + VEGF, MMP-9 + VEGF, p53 + VEGF) was 62.4% in frequency and revealed increased tendency in advanced cancer than early cancer. VEGF expression showed to portend a short survival among patients with non-small cell lung cancer (p=0.05). Conclusion: These results suggested that COX-2 overexpression might be an indicator of an unfavorable clinical outcome and VEGF overexpression appears to portend a short survival. However, further studies of a possibility of prognostic significance, such as MMP-9, p53 and synchronous production of gene products, are required for the determination of significant relationship in other clinicopathologic indices.

돌돔, Oplegnathus fasciatus의 Cyclooxygenase-2 유전자의 cloning 및 발현분석

진지웅 ( Ji Woong Jin ),김도형 ( Do Hyung Kim ),김영철 ( Young Chul Kim ),정현도 ( Hyun Do Jeong ) 한국어병학회 2013 한국어병학회지 Vol.26 No.1

Megalocytivirus는 우리나라를 포함한 아시아 각국의 양식현장에서 고위험성 병원체이다. 그럼에도 불구하고 어류의 면역체계와 megalocytivirus의 상호관계에 관한 연구는 아직 부족한 실정이다. 다양한 연구에서 cyclooxygenase isoform중 COX-1 유전자는 constitutive 하게 발현되며, COX-2 enzyme은 면역반응에 중요한 역할을 한다고 알려져 있다. 또한 COX-2유전자는 LPS (lipopolysaccharide) 또는 병원체의 감염과 같은 염증반응 시 그 발현이 증가한다고 알려져있다. 본 연구는 다른 어종의 COX-2 유전자를 바탕으로 제작된 degenerated primer와 5``- 그리고 3``-end RACE-PCR을 이용하여 돌돔에서 COX-2 유전자의 전체 염기서열을 밝혔으며, 그 결과 rbCOX-2 (rock bream COX-2)유전자 cDNA의 전체 길이는 2655 bp 였으며, 609개의 아미노산으로 구성되어있었다. rbCOX-2 유전자의 genomic organization은 9개의 intron과 10개의 exon으로 구성되어 있었다. 또한 본 연구에서는 돌돔에 megalocytivirus의 인위감염 시 COX-2 유전자의 발현을 조사하였다. LPS 접종 시 rbCOX-2 유전자는 접종1일 후 대조구와 비교하여 13.10배 증가하여 최고 발현을 보였으나, megalocytivirus 접종 시 대조구와의 비교에서 유의적인 발현을 확인할 수 없었다. 돌돔에서 COX-2 유전자의 염기서열의 분석과 발현 분석은 바이러스 감염 시 어류의 방어기작을 이해하는데 도움이 될 것이며, 바이러스 백신개발 및 치료제 개발의 기초자료로 활용될 것이다. Megalocytivirus is a major fish pathogen in marine aquaculture of Asian countries including Korea. Despite of many species affected by this pathogen, little is known interaction between megalocytivirus and the fish immune system. One of the cyclooxygenase isoforms, named COX-2, is playing an important role in immune regulation, and distinct from COX-1 isoform of constitutive activity. COX-2 enzyme is induced by various inflammatory signals, including injection of lipopolysaccharide or infection by pathogenic agents. We cloned COX-2 gene in rock bream using degenerated primers designed from reported sequences of other fish species in PCR followed with 5``- and 3``-end RACE-PCR. The full length of cDNA of rbCOX2 (rock bream COX-2) gene are 2655 bp and that translates into 609 amino acids. The rbCOX-2 genomic organization are found to span 10 exons separated by 9 introns. We also studied if the experimental infection of rock bream with megalocytivirus could affect the expression of COX-2 gene. When injected with LPS, expression of the COX-2 gene was reached peak level at 1 day post injection and showed b13.10 fold increased level compared with that of control. While, when injected with megalocytivirus, we were not able to find significantly increased COX-2 gene expression different from that of control. Cloned and analyzed COX-2 gene in rock bream will help to understand defence mechanisms in fish after viral infection and will also support the development of the measures for treatment and prevention of viral infection.

자궁경부암에서의 COX-2 와 VEGF 발현에 관한 연구

박성재 ( Park Seong Jae ),이선경 ( Lee Seon Gyeong ),이주희 ( Lee Ju Hui ),김승보 ( Kim Seung Bo ) 대한산부인과학회 2004 Obstetrics & Gynecology Science Vol.47 No.5

목적 : 자궁 경부암을 포함하여 여러 악성 종양에서 cyclooxygenase-2 (COX-2)의 과발현이 종양형성의 단계에 관련 있다고 보고되고 있다. COX는 prostaglandin형성에 관여하는 효소인데 두 도가지 이성체가 알려져 있다. 평소에는 정상조직에서는 거의 발현되지 않는 혈관신생과 관련하여 종양형성에 관여하는 COX-2와 과발현의 유발은 조직의 저산소증에 의해 조절되는 것으로 알려져 있으며, 이런 저산소증은 vascular endothelial growth factor (VEGF)의 발현을 유발한다고 한다. 이에 저자들은 자궁경부암중 침윤성암 25예, 미세침윤성암 7예, 그리고 상피내암종 9예의 조직에서 COX-2 및 VEGF의 과발현과 미세혈관밀도의 상관관계를 알아보고자 하였다. 연구 방법 : 1999년 1월부터 2001년 12월까지 경희대학교 산부인과에서 자궁경부암으로 진단받은 41예와 정상자궁경부 조직 4예를 대상으로 COX-2 단클론성 항체와 Rabbit anti-human VEGF 항체를 이용하여 면역조직 화학 염색을 시행하였다. 또한 factor Ⅷ 항체를 이용하여 미세혈관밀도를 측정하였다. COX-2와 VEGF의 면역조직화학적 염색결과는 면역반응의 염색 강도와 염색된 세포의 수에 따라 음성 (0), 약양성 (light staining, 1), 중간양성 (moderate staining, 2), 강양성 (heavy staining, 3)으로 반정량적 판독을 하였다. 결과 : COX-2 면역반응은 상피세포 기저막과 암 침윤부위가 특히 강하게 발현되는 것을 볼 수 있었다. 그리고 상피내암종, 미세침윤성 자궁경부암, 침윤성 자궁경부암으로 갈수록 강양성의 반응도가 증가하는 것을 관찰할 수 있었고 (p=0.006), VEGF 면역반응 역시 암이 진행할수록 양성의 빈도가 증가하는 경향을 확인하였다 (p=0.079). 이들 COX-2 면역반응과 VEGF 면역반응은 상관관계가 있는 것으로 확인되었다 (r_(s)=0.686, p<0.01). 또한 이들의 면역반응은 미세혈관 밀도와 상관관계를 보이는 것으로 관찰되었다. 결론 : COX-2와 VEGF의 발현이 자궁경부 종양의 발생초기 단계에 중요한 상호역할을 하는 것으로 사료된다. Objective : The purpose of this study was to know the potential of growth, invasion and metastasis of uterine cervical cancer associated with neovascularization and to investigate whether the enhanced COX-2 (Cyclooxygenase-2) and VEGF (Vascular Endothelial Growth Factor) expression is showed through CIS to invasive cervical cancer and to examine that COX-2 and VEGF expressions are associated with prognostically worse pathological variables and had a direct correlation with tumor MVD (microvessel density). Methods : From January 1999 to December 2001, 45 paraffin-embedded cervical specimens were obtained by surgical resection in the Kyung Hee University Medical Center. The study group included 25 cases in invasive squamous carcinomas, 7 cases in microinvasive carcinoma, 9 cases in carcinoma in situ, 4 cases in the benign uterine diseases. All tissues were subjected to immunohistochemical staining for COX-2, VEGF and microvessel density (MVD), and immunostaining was scored using a four-point scale with (0) indicating no expression, (1) light staining, (2) moderate staining, (3) heavy staining. Results : As the cervical tumorigenesis progressed, there was a significant increase of MVC (microvessel count) and COX-2 expression. There is a significant correlation between COX-2 and VEGF expression (r_(s)=0.686, p<0.01) in cervical neoplasms. There was no correlation between COX-2, VEGF expression and clinicopathologic factors in cervical cancer. Conclusion : These findings provide evidence that the expression of COX-2 and VEGF is involved in the promotion of angiogenesis in cervical neoplasms and plays an important role in early invasion.

자궁경부암 및 상피내암 조직에서의 인유두종바이러스와 Cyclooxygenase 2 과발현의 상관관계

최윤석 ( Youn Seok Choi ),이태성 ( Tae Sung Lee ),김주현 ( Ju Hyun Kim ),김홍태 ( Hong Tae Kim ),오훈규 ( Hun Kyu Oh ),한치동 ( Chi Dong Han ) 대한산부인과학회 2008 Obstetrics & Gynecology Science Vol.51 No.8

목적: 자궁경부암 및 자궁경부 상피내암에서 인유두종바이러스 (HPV)와 cyclooxygenase 2 (COX-2) 발현과의 상관 관계를 알아보고자 하였다. 방법: 각각 14명씩의 자궁경부 상피내암, 자궁경부암 환자의 자궁경부 조직과, 대조군으로는 자궁근종으로 자궁적출술을 받은 14명의 환자들의 자궁경부 조직을 이용하였다. 인유두종바이러스 검출에는 중합효소연쇄반응을 이용하였고, COX-2 검출에는 면역조직화학적 염색을 이용하였다. 결과: 고위험군의 인유두종바이러스 감염은 대조군에 비해 상피내암과 자궁경부암에서 현저히 많이 검출되었다 [상피내암: 11예 (78.6%), 자궁경부암: 14예 (100%), 대조군: 1예 (7.1%), P-value<0.001]. COX-2의 발현 강도는 대조군보다 상피내암이 높았고 (P=0.037), 자궁경부암이 상피내암보다 더 높았다 (P=0.002). 인유두종바이러스가 검출되지 않았던 상피내암 3예에서는 바이러스가 검출되었던 나머지 상피내암에 비하여 COX-2의 발현이 현저히 낮게 나타났다 (P=0.013). COX-2의 발현정도와 인유두종바이러스감염과는 유의한 상관관계를 보였으나 (P<0.001), 다변량 분석에서는 정상 조직에서 상피내암, 침윤암으로의 진행만이 COX-2 과발현에 독립적으로 영향을 주는 인자였다. 결론: COX-2의 과발현에는 정상조직에서 침윤암으로의 진행정도가 고위험 인유두종바이러스감염보다 더 중요한 요인으로 추정된다. Objective: The aim of this study was to identify the relation between HPV infection and cyclooxygenase 2 (COX-2) overexpression in cervical carcinoma in situ (CIS) and carcinoma. Methods: Fourteen patients with CIS, 14 patients with invasive cervical carcinoma, and 14 patients with myoma as control were enrolled. Polymerase chain reaction was used to detect high risk types of HPV, and immunohistochemistry was used to detect COX-2 expression. Results: The frequencies of high risk types of HPV infections in CIS or carcinoma were significantly higher than control [CIS: 11 (78.6%), carcinoma: 14 (100%), control: 1 (7.1%), P-value<0.001]. COX-2 expressions in CIS were higher than control (P=0.037), and those in carcinoma were higher than CIS (P=0.002). Three patients with CIS did not show HPV infection and showed lower COX-2 expression than the other patients with HPV infection in CIS group (P=0.013). There was strong correlation between COX-2 expression and HPV infection (P<0.001). However, in multivariate analysis, disease progression from normal to invasive carcinoma was the only independent factor to affect COX-2 overexpression. Conclusion: Disease progression from normal to invasive carcinoma might be more important factor to affect COX-2 overexpression than high risk types of HPV infection.