흰쥐 콩팥 세관 상피 세포에서 E-cadherin의 발현

황인아(In-A Hwang),하헌주(Hunjoo Ha),한기환(Ki-Hwan Han) 대한해부학회 2008 Anatomy & Cell Biology Vol.41 No.1

E-cadherin은 상피세포의 이음복합체에 존재하는 주요접합분자이며, 상피세포의 극성을 유지하고 세포간 상호작용을 담당한다. E-cadherin은 콩팥에서 발현되는 것으로 알려져 있으나 세관에 따른 정확한 발현양상은 아직 알려져 있지 않다. 본 연구의 목적은 콩팥세관에 따른 E-cadherin의 발현양상을 관찰하는 것이다. Sprague-Dawley계 흰쥐의 콩팥을 분리하여 면역조직화학염색과 western blot을 실시하였다. 세관에 따른 E-cadherin의 분포를 관찰하기 위해 세관 상피세포의 지표인 bumetanide-sensitive Na+/K+/2Clcotransporter(BSC1), thiazide-sensitive Na+/Cl- cotranstporter(TSC), calbindinD28k, H+-ATPase과 함께 이중염색을 실시하였다. 흰쥐 콩팥에서 E-cadherin은 상피세포의 기저외측막에서 발현되었다. 집합관과 콩팥유두상피세포에서 강하게 발현되었고, 근위곱슬세관, 헨레고리, 헨레고리의 내림가는부분에서 약하게 발현되었다. 원위곱슬세관과 헨레고리의 굵은오름부분에서 중간 정도의 발현을 보였으며, 핵하부세포질에 퍼져있는 양상으로 발현되었다. 토리상피세포와 근위곧은세관에서 E-cadherin이 발현되지 않았다. E-cadherin의 단백정량결과 겉질과 바깥속질에 비해 속속질에서 E-cadherin이 많이 발현되었다. 이상의 결과로 E-cadherin은 콩팥세관 상피세포에 따라 다른 발현양상을 보이며, 집합관과 콩팥유두상피세포에서 주요 접합분자로 작용함을 알 수 있었다. E-cadherin is a cell adhesion molecule that is expressed abundantly in the kidney. However, the expression pattern in various renal epithelial cells is not well established. The purpose of this study was to determine the cellular localization along the nephron segments in the rat kidney. Kidneys from adult Sprague Dawley rats were fixed in 4% paraformaldehyde and processed for immunohistochemistry. Bumetanide-sensitive Na+/K+/2Cl- cotransporter (BSC1), thiazide-sensitive Na+/Cl- cotransporter (TSC), calbindin D28k, and H+-ATPase were used to identify the thick ascending, distal convoluted stubule, connecting tubule, and collecting duct, respectively. In the rat kidney, Ecadherin was expressed mainly in the basolateral domain of the collecting duct and papillary surface epithelial cells. The expression level of E-cadherin changed gradually in the connecting tubule and became moderate in the distal convoluted tubule, thick ascending limb, and loop of Henle. The S1 and S2 segment of the proximal tubule showed weak immunoreactivity. However, E-cadherin was not expressed in the S3 segment of the proximal tubule in the rat kidney. These results suggest that E-cadherin is a major adhesion molecule in the collecting duct and papillary surface epithelium, and that E-cadherin may play a critical role in maintaining the epithelial polarity of these nephron segments.

자궁내막암과 자궁내막증식증에서 E-cadherin 발현과 유전자 돌연변이에 관한 연구

박지현 ( Jee Hyun Park ),조성진 ( Seong Jin Cho ),황성욱 ( Sung Ook Hwang ),송은섭 ( Eun Seop Song ),임문환 ( Moon Whan Im ),이병익 ( Byoung Ick Lee ),이우영 ( Woo Young Lee ) 대한산부인과학회 2009 Obstetrics & Gynecology Science Vol.52 No.3

Objective: Reduced tumor cell adhesion is associated with invasive growth and unfavorable prognosis. In endometrial carcinoma, the prognostic impact of adhesion marker such as E-cadherin is partly known. The purpose of this study is to investigate the correlation of the expression and the mutation of E-cadherin in endometrioid endometrial adenocarcinomas and endometrial hyperplasias and to correlate their results with various clinicopathological factors. Methods: The expression of E-cadherin by using immunohistochemical staining (IHC) and the mutation of E-cadherin gene by using polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) and sequencing were performed in tissues of 20 endometrial adenocarcinomas and 30 endometrial hyperplasias. The results were compared with previously known prognostic factors such as the stage, tumor grade and lymph node metastasis. Results: Decreased expression of E-cadherin was detected in 13 of 30 (43.3%) endometrial carcinomas and in 1 of 20 (5%) endometrial hyperplasias (P=0.009). There was no statistical significance of the mutation of E-cadherin gene in between the endometrial carcinomas and endometrial hyperplasias (6.7%: 0%) (P=0.06). The incidence of the expression loss of E-cadherin in endometrial carcinomas also showed significantly higher with tumor grade 3, tumor stage above Ic or lymph nodal metastasis (P=0.01, P=0.02, P=0.03). Conclusion: Decreased expression of E-cadherin was detected significantly higher in endometrial carcinomas than endometrial hyperplasias. And the incidence of decreased expression of E-cadherin was more frequent in advanced stage, high histopathologic grade, and lymph nodal metasis. The mutation of E-cadherin gene was detected in only 2 cases. These results suggests that the expression of E-cadherin seems to be important in endometrial carcinomas and associated with aggressive subgroups. But the mutation of E-cadherin gene would not be related to endometrial carcinomas.

자궁경부 암화과정에서의 E-cadherin 발현에 관한 연구

문혜성(HS Moon),김종일(JI Kim),손영숙(YS Son),김병기(BG Kim),박상윤(SY Park) 대한산부인과학회 1997 Obstetrics & Gynecology Science Vol.40 No.3

Objectives : E-cadherin is the prime mediator of cell-cell adhesion in epithelial cells and its loss may be important in tumor spread. The present study was aimed to find the role of E-cadherin in cervical carcinogenesis, and to assess the clinical value of serum soluble E-cadherin in diagnosing or monitoring the progression of cervical cancer. Methods : The subjects of this study included the serums and paraffin blocks of cervix in women with normal cervix(16 cases), and patients with moderate dysplasia(4 cases), severe dysplasia(10 cases), CIS(8 cases), keratinizing cervical carcinoma(5 cases), and nonkeratinizing cervical carcinoma(8 cases). For in vitro assay, cervical cancer cell lines, e.g.C-33A, CaSki, SiHa and HeLa cell lines were used. The serum levels of E-cadherin in women were measured by enzyme immunoassay, Every paraffin block of cervix was stained for E-cadherin by immunohistochemical staining. After culture of 4 cervical cancer cell lines, immunocytochemical staing for E-cadherin was tried by raft cultured cell lined. Results : There was no differences in the serum level of E-cadherin among the women who had the normal cervix, patients with moderate dysplasia, patients with severe dysplasia, patients with CIS of cervix, and patients with keratinzing cervical carcinoma and nonkeratinizing cervical carcinoma. Loss of E-cadherin expression was closely related with the grade of dysplasia of cervix and the differentiation of cervical cancer(p<0.05). E-cadherin was strongly expressed in the basal layer and suprabasal layer of the normal cervix, but its expression was shown in the other tissue layers of dysplasia of cervix(p<0.05). The cytoplasmic E-cadherin expression was related to membranous expression and it was correlated with the grade of dysplasia of cervix and the defferentiation of cervix cancer(p<0.001). In raft culture of 4 cervical cancer cell lines, all cancer cell lines except CaSki cell line were well grown at the air-liquid interface. There was negative E-cadherin expression in raft cultured cell lines. Conclusion : It is considered that first, E-cadherin has a role in cervical carcinogenesis, its loss is related with the grade of dysplasia of cervix and the differentiation of cervical cancer. However measuring soluble E-cadherin level may not reflect the progression of cervical cancer accurately.

Syndecan-2 enhances E-cadherin shedding and fibroblast-like morphological changes by inducing MMP-7 expression in colon cancer cells

Jang, Bohee,Jung, Hyejung,Chung, Heesung,Moon, Byung-In,Oh, Eok-Soo Elsevier 2016 Biochemical and biophysical research communication Vol.477 No.1

<P><B>Abstract</B></P> <P>E-cadherin plays a mechanical role in mediating cell-cell interactions and maintaining epithelial tissue integrity, and the loss of E-cadherin function has been implicated in cancer progression and metastasis. Syndecan-2, a cell-surface heparan sulfate proteoglycan, is upregulated during the development of colon cancer. Here, we assessed the functional relationship between E-cadherin and syndecan-2. We found that stable overexpression of syndecan-2 in a human colorectal adenocarcinoma cell line (HT29) enhanced the proteolytic shedding of E-cadherin to conditioned-media. Either knockdown of matrix metalloproteinase 7 (MMP-7) or inhibition of MMP-7 activity using GM6001 significantly reduced the extracellular shedding of E-cadherin, suggesting that syndecan-2 mediates E-cadherin shedding via MMP-7. Consistent with this notion, enhancement of MMP-7 expression by interleukin-1α treatment increased the shedding of E-cadherin. Conversely, the specific reduction of either syndecan-2 or MMP-7 reduced the shedding of E-cadherin. HT29 cells overexpressing syndecan-2 showed significantly lower cell-surface expression of E-cadherin, decreased cell-cell contact, a more fibroblastic cell morphology, and increased expression levels of ZEB-1. Taken together, these data suggest that syndecan-2 induces extracellular shedding of E-cadherin and supports the acquisition of a fibroblast-like morphology by regulating MMP-7 expression in a colon cancer cell line.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Syndecan-2 enhances E-cadherin proteolysis in human colon cancer cells. </LI> <LI> Syndecan-2 regulates E-cadherin shedding through MMP-7 expression. </LI> <LI> Syndecan-2-mediated E-cadherin shedding induces fibroblast-like morphological changes. </LI> </UL> </P>

대장암의 E-cadherin의 발현양상

배병진,박성대,배옥석 啓明大學校 醫科大學 2001 계명의대학술지 Vol.20 No.2

대장암에서의 E-cadherin의 역할을 알아보기 위하여 면역조직화학적 염색을 실시하여 E-cadherin의 발현 정도에 따른 임상병리학적 연관성을 비교하여 보았다. 정상 조직과 암 조직을 비교한 23례 중에서 9례가 발현이 감소되었고, 23례 중에서 혈관 침습 16례, 신경 침습 8례 였다. E-cadherin 발현 저하와 혈관침습, 신경 침습 사이의 통계학적 연관성은 유의 한 것으로 나타나 대장암에서의 E-cadherin의 발현 저하는 주위 조직 침습에 영향을 주는 인자로 생각할 수 있다. E-cadherin을 종양 진행의 표지자로 활용하기 위해서는 E-cadherin의 말단부에 위치한 catenin에 대한 연구와 유전자적인 세부 구조에 대한 연구가 더 필요할 것으로 사료된다. Tumor invasion and it's metastasis are the major causes of the failure of treatment in colorectal cancer patients. E-cadherin, thought to be related to invasion and metastasis in colorectal cancer, is a cell-cell adhesion molecule found mainly in epithelial tissues. The expression of E-cadherin was evaluated in 23 colorectal cancer patients. In order to stain colon cancer tissues and normal colonic mucosa simultaneously on the same slides and to reduce a personal error during immnunohistochemical staining procedure, we took colonic cancer tissues which had normal colonic mucosa right after surgery. The expression of E-cadherin in colorectal cancers was investigated using immunohistochemical staining method. We defined two experimental groups as follows. A: the intensity of E-cadherin expression in cancer was significantly reduced, when compared with that of normal colonic mucosa. B : Little difference between the two tissues in the expression of E-cadherin. Of 23 cases, 9 cases belonged to A group, and 14 cases belonged to B group. The number of cases with vascular and neural invasion of the tumor was significantly higher in A group than in B group. The expression of E-cadherin was reduced in tumors with lymph node metastasis, but the results was not statistically significat. Above results indicate that the loss of E-cadherin expression in colorectal cancers may be related to tumor invasion to adjacent tissues.

소아에서 발생한 대장의 염증성 질환에서 E-cadherin의 발현

이나영,박도윤,박재홍,Lee, Na-Young,Park, Do-Youn,Park, Jae-Hong 대한소아소화기영양학회 2009 Pediatric gastroenterology, hepatology & nutrition Vol.12 No.2

목 적: 소아에서 다양한 원인에 의해 발생한 대장염에서 점막의 형태학적 변화와 세포 접합에 다양한 변화가 있으리라 예상되어 세포 간의 결합을 유지하는 E-cadherin의 변화를 살펴보았다. 방 법: 1998년 1월부터 2003년 8월까지 부산대학교병원 소아청소년과에서 하부 위장관 내시경술과 대장점막 조직 검사를 통해 대장염으로 진단된 39명을 대상으로 하였다. 파라핀 블록에서 면역조직화학염색법을 이용하여 E-cadherin의 세포 내 발현을 조사하였다. 주변의 정상 조직과 비교하여 E-cadherin의 발현이 동일한 강도와 양상을 가진 세포가 50% 이상인 경우를 정상으로 판정하였고, 발현이 정상인 세포가 50% 미만이거나 염색 분포의 이상이 있거나 전혀 염색되지 않은 경우를 이상으로 판정하였다. 결 과: 1) 본 연구에서 비특이성 대장염 15예(38.5%), 크론병 7예(17.9%), 감염성 대장염 5예(12.8%), 음식 단백 과민성 직결장염 5예(12.8%), 궤양성 대장염 3예(7.7%), Henoch-Schonlein purpura 대장염 2예(5.1%), 그외 베체트병, 허혈성 대장염 1예가 포함되었다. 2) 모든 종류의 대장염에서 상피세포 E-cadherin 발현 감소가 관찰되었으며, 77%의 대상 표본에서 E-cadherin 발현감소가 있었다. 3) 활동성 염증이 심한 부위에서 Ecadherin 발현 감소가 현저하였으며 병변부에서 떨어진 상피세포에서는 정상 발현을, 궤양 주위나 재생 상피가 있는 부위는 심한 발현 감소를 보였다. 결 론: 모든 종류의 염증성 대장 질환에서 E-cadherin 발현 감소가 있었다. 이러한 변화는 염증과 궤양이 있는 부위에서 상피세포 접합을 느슨하게 함으로써 상피세포의 재생을 위한 세포의 이동을 용이하게 하기 위한 작용이라고 판단된다. Purpose: Colitis is a condition associated with a spectrum of altered morphologic changes and cellular adhesion. E-cadherin plays a key role in the establishment and maintenance of epithelial tissue structure and cell-cell adhesion. The purpose of this study is to evaluate E-cadherin expression in colonic epithelium of various colitis in children. Methods: The expressions of E-cadherin were examined in 39 cases of colonic mucosal biopsy specimen using immunohistochemical staining. When more than 50 percent of cells exhibited uniformly the same intensity and pattern of immunostaining as the adjacent normal mucosa, the antigen expression was considered normal. Abnormal expression was defined when less than 50 percent of cells stained, when cells showed a heterogeneously weak or altered distribution, or when complete absence of staining was observed. Results: Fifteen cases with non-specific colitis (38.5%), 7 cases of with Crohn's disease (17.9%), 5 cases of infectious colitis and milk protein sensitive proctocolitis (12.8%), 3 cases of ulcerative colitis (7.7%), 2 cases of Henoch-Schonlein purpura colitis (5.1%), one case of Behcet's disease and ischemic colitis (2.6%) were included in this study. E-cadherin expression was decreased in all kinds of colitis. Reduced expression of E-cadherin was observed in 77 percent of cases. E-cadherin was weaker or no expression in reparative epithelium and "ulcer associated cell lineage". Conclusion: Altered expression of E-cadherin occurs during mucosal inflammation in any kinds of colitis. These changes may be involved in promoting cell migration during epithelial restitution of the gastrointestinal mucosa.

E-cadherin regulates integrin signal pathway through β-catenin in gastric adenocarcinoma

Lim, Sung-chul,Lim, Kyung-joon 조선대학교 부설 의학연구소 2002 The Medical Journal of Chosun University Vol.27 No.2

배경: E-cadherin은 상피세포의 세포-세포 부착에 관여하며 암세포에서 해당 유전자는 대개 돌연변이가 초래되거나 낮게 발현된다. E-cadherin의 과발현은 여러 가지 integrin family의 발현을 감소시킨다는 보고가 있지만 어떻게 E-cadherin이 integrin에 영향을 미치는지, E-cadherin이 integrin과 관련된 신호물질에 어떠한 영향을 미지는지에 관해서 확실하게 밝혀진 바가 없다. 재료 및 방법: 조선대학교 부속병원에서 1997년 부터 1999년까지 진행성 위 선암종으로 위절제술을 받은 환자를 대상으로 E-cadherin에 대한 면역조직화학적 염색을 시행하여 과발현 (정상 발현 또는 과발현)을 보이는 군과 저발현 (비발현 또는 저발현)을 보이는 군을 각각 30명씩 연속적으로 선택하였다. 이들을 대상으로 βatenin과 integrin, 그리고 cyclin D1에 대한 면역조직화학적 염색을 시행하여 비교 분석하였다. 결과: E-cadherin 과발현은 cyclin D1, integrin, 그리고 P-catenin의 발현을 유의하게 감소시키며, βatenin 발현은 integrin 발현을 유의하게 증가시켰다. 결론: E-cadherin 과발현은 βatenin을 감소시켜 integrin 신호전달체계와 cyclin D1 발현을 억제할 수 있을 것으로 판단된다. Background and Objectives: E-cadherin mediates cell-cell adhesion in epithelial cells and its gene is usually mutated or lowly expressed in carcinoma cells. It has been reported that over-expression of E-cadherin can reduce the expression of several members of integrin family, such as α2β1 and α3β1 But it was still not clear how E-cadherin influences integrin or whether E-cadherin can influence the signal molecules in downstream of integrin. Materials and Methods: The authors analyzed the patterns of integrin expression along with the interrelation between E-cadherin and, βatenin, and cyclin D1 expression in 60 cases of advanced gastric adenocarcinoma, in patients who received gastric resection from 1997 to 1999. Of them, the number of E-cadherin over-expressed (normal- or over-expressed) cases was 30, and the number of E-cadherin under-expressed (non- or under-expressed) cases was 30. Results: The authors found that over-expression of E-cadherin could reduce the expression of cyclin Dl, which is a key protein related to cell cycle, in comparison with the E-cadherin under-expressed group. In correspondingly, the stainability of, β, and α5- integrins was declined significantly in the E-cadherin over-expressed group compared with the E-cadherin under-expressed group. βatenin expression in the E-cadherin over-expressed group was also decreased significantly in comparison with the E-cadherin under-expressed group. Positive expression of integrin was increased significantly in the βatenin expressed cases compared with the βatenin non-expressed cases. Conclusion: The results suggested that over-expression of E-cadherin can suppress the integrin signaling pathway and the expression of cyclin D1 through decreasing βatenin level.

자궁경부암에서 종양진행과 E-cadherin/α-catenin 발현이상에 관한 연구

김정식,허진숙,김홍배,심정원,전현아,이근영,강성원 대한부인종양 콜포스코피학회 2003 Journal of Gynecologic Oncology Vol.14 No.2

목적 : E-cadherins은 상피특이적이고 칼슘 의존적 세포간 부착에 관여하는 막간 당단백질군에 속한다. E-cadherin의 기능은 그것과 세포질에서 연결되는 α-catenin에 의해 조절된다. α-catenin은 actin과 E-cadherin을 연결시킨다. 이 연구는 E-cadherin a/α-catenin의 발현이 양성자궁질환, 상피내암, 침윤암에서 어떤 차이를 보이는지 알아보는 것이다. 연구 방법 : 89개의 조직표본을 펀치생검, 원추 절제술, 자궁적출술에 의해 얻었다. 절편은 FIGO staging에 따라 양성 경부, 상피내암, 침윤암으로 분류되었다. E-cadherin/α-catenin의 발현은 monoclonal antibody로 면역조직화학 염색을 하여 조사하였다. 세 군간의 E-cadherin/α-catenin의 발현양상을 조사했다. 통계적 의미를 조사하기 위해 x² test를 이용했다. 결과 : E-cadherin에서는 정상염색(normal), 낮은 양성(low-positive), 이종(異種, heterogeneous)염색, 음성(negative) 염색 결과가 양성 질환인 경우 각각 19, 1, 0, 2예, 상피내암인 경우 12, 5, 3, 4예, 침윤암인 경우 10, 8, 20, 5예를보였다. α-catenin에서도 양성 질환인 경우 각각 18, 1, 1, 2예, 상피내암인 경우 9, 9, 4, 2예, 침윤암인 경우 8, 8, 19, 8예를 보였다. 조직검사와 E-cadherin과 α-catenin의 발현강도와 분포사이에 통계적으로 의미있는 상관관계 (χ² test, p<0.0001)를 보였다. 즉 양성질환 보다 상피내암, 침윤암일 수록 두 물질의 비정상적인 발현양상을 관찰할 수 있었고, E-cadherin/α-catenin의 발현도 변화와 조직학적 진단간에 상관관계가 있었다. 결론 : 이 결과에 따라 저자는 자궁경부암에서 종양진행에 따라 E-cadherin/α-catenin의 발현에 있어서 분포와 강도가 변화함을 알게 되었다. Objective : E-cadherins are a family of transmembrane glycoproteins involved in epithelial specific and calcium-dependent intercellular adhesion. E-cadherin function is regulated by its associated cytoplasmic protein, α-catenin, which links E-cadherin to the actin-based cytoskeleton. This study is to determine what lack and differrence in expression of E-cadherin and α-catenin between benign, CIS, and invasive carcinoma of uterine cervix. Methods : 89 tissue specimens were obtained by punch biopsy, conization, and hysterectomies. Sections were classified according to FIGO staging as benign cervix, carcinoma in situ, invasive cervical carcinoma. The expression of E-cadherin and α-catenin was examined immunohistochemically with monoclonal antibodies. What degree in expression of E-cadherin and α-catenin in three group was investigated. The χ² test was used to assess the statistical significance of this study. Results : The correlation between the altered expression of E-cadherin/α-catenin and the histopathologic diagnosis was statistically significant. Conclusion : According to this result, we found that the distribution and intensity in expression of E-cadherin and α-catenin is altered during tumor progression of cervical carcinoma.

간세포암의 조직학적 분화도 및 임상적 특징에 따른 E-cadherin과 β-catenin의 발현 양상

배시현,정은선,박영민,장정원,최종영,조세현,윤승규,안병민,차상복,정규원,선희식,박두호,김병기,김동구 대한간학회 2002 Clinical and Molecular Hepatology(대한간학회지) Vol.8 No.3

배경/목적: E-cadherin과 β-catenin은 하나의 복합체를 형성하여 세포간 접착을 유지하는데 중요한 기능을 하고, 이들의 돌연변이는 세포간 접착기능의 상실로 종양의 발생과 세포전이를 유도한다. 본 연구의 목적은 간세포암 조직에서 E-cadherin과 β-catenin의 발현 양상과 빈도를 조사하고, 간세포 암의 임상적, 병리학적 인자들 사이에 상호관련성을 알아보고자 하였다. 방법: 간세포암으로 진단받은 36 명의 환자로부터 수술후 얻은 파라핀 포매된 조직을 대상으로 E-cadherin과 β-catenin에 대한 면역조직화학적 염색을 시행하였다. E-cadherin의 발현은 세포질막의 염색유무로 분류하였고, β -catenin의 발현은 세포질형과 핵형으로 분류하였다. 간세포암의 발생 원인, 혈청 AFP 수치, TNM stage, 간세포암의 크기, 형태적 유형, 다른 장기 전이, 간세포암의 분화도 및 간문맥 혈전 유무 등에 대해서도 분석하였다. 결과: 간세포암 부위에서 E-cadherin의 발현은 세포질막 발현이 58% (21/ 36), 발현이 안되는 경우가 42%(15/36) 였다. β -catenin의 발현은 세포질형 83%(30/36)와 핵형 14%(5/36), 그리고 염색이 안된 경우가 3%(1/36) 였다. 간세포암의 고, 중, 저 분화도에 따른 E-cadherin, β-catenin 의 발현 양상 사이에 상호 관련성은 관 찰할 수 없었다 결론: 간세포암에서 주변 비간암 조직에 비교해서 E-cadheirn의 발현감소를 관찰할 수 있었으며, β-catenin의 핵내 발현이 증가되어 E-cadherin, β-catenin system이 간세포암 발생 과정에 관련이 있음을 알 수 있었다. 간세포암 분화도, 간세포암의 임상적인 특징에 따른 E-cadherin 및 β-catenin의 발현 양상차이는 없었다. Background/Aims: E-cadherin is involved in intercellular binding and cellular polarity formation. β-catenin plays a fundamental role in regulation of the E-cadherin cell adhesion complex. The abnormalities of the components of the complex may disrupt this adhesive function. We investigated the expression patterns of E-cadherin and β-catenin to determine the clinical significance of these proteins in hepatocellular carcinoma. Materials/Methods: Thirty-six hepaticellular carcinoma tissues and adjacent non-tumor specimens were analyzed. Subcellular distribution of E-cadherin and β-catenin was examined by immunohistochemistry staining. We evaluated the patterns of the expression, and investigated the relationship with the cause of HCC; level of AFP; TNM stage; tumor size; growth types; metastasis; differentiation grade of HCC; and presence of portal vein thrombosis. Results: Immunohistochemistry showed that all non-tumor tissues had membranous type staining of E-cadherin. All non-tumor tissues showed cytoplasmic type staining of β-catenin, but no β -catenin accumulation in nuclei was found. 58% (21/36) of HCC showed positive expression of E-cadherin in cytoplasmic membrane. The cytoplasmic expression of β-catenin in HCC was 83% (30/36); nuclear expression in 14% (5/36); and no staining in 3% (1/36). Nuclear β-catenin expression was observed in none (0/4) of the well-differentiated HCC; 17%(3/9) of moderate-differentiated HCC; and 17%(2/6) of poorly-differentiated HCC. There were no relationships between E-cadherin and β-catenin expression with other clinicopathologic factors. Conclusions: Loss of cytoplasmic staining of E-cadherin and nuclear accumulation of β-catenin were observed in HCC. Nuclear accumulation of β-catenin was not found in well differentiated HCC but was found in poorly differentiated HCC. (Korean J Hepatol 2002;8:297-303)

한국인 위암 조직의 E-cadherin 유전자 촉진자 과메틸화

박미경,김헌 충북대학교 의과대학 충북대학교 의학연구소 2003 忠北醫大學術誌 Vol.13 No.2

연구목적: 위암은 우리 나라에서 가장 흔한 암으로서, E-cadherin 유전자의 촉진자 과메틸화가 전체 위암 환자 위암 조직의 50% 이상에서 나타난다. E-cadherin 유전자 촉진자 과메틸화가 있는 위암에서는 E-cadherin 유전자 발현이 현저히 감소되며, 이에 따라 암의 침습과 전이가 유발될 가능성이 높다. 한편, 숙주의 감수성과 밀접한 관련이 있는 각종 유전자 다형성과 환경적 요인인 식이습관은 E-cadherin 유전자 촉진자 과메틸화를 유발할 가능성이 높다. 이에 본 연구자는 IL-1 와 GSTP1 유전자 다형성과 식이 습관이 E-cadherin 유전자 촉진자의 과메틸화에 미치는 영향을 파악하고, 궁극적으로는 위암발생에 미치는 영향을 알아보고자 하였다. 대상 및 방법 : 조직학적으로 위암으로 진단 받은 환자 110명과, 이들과 1:2로 성과 연령 을 짝지은 대조군 220명을 모집하고, 이들에 대하여 식이 습관과 음주, 그리고 흡연 등 위암의 위험요인 폭로에 대한 직접 면접조사를 실시하였다. 모든 대상자에 대하여 IL-1 와 GSTP1 유전자 다형성을 PCR-RFLP 방법으로 조사하였다. 위암 조직에서 추출한 DNA를 이용하여 methylation-specific PCR 방법으로 E-cadherin 유전자 촉진자의 과메틸화 여부를 확인하였다. 결과: 위암환자 110명 중 44명(40%)의 위암조직에서 E-cadherin 유전자 촉진자의 과메틸화가 나타났다. E-cadherin 유전자 촉진자의 과메틸화와 IL-1 와 GSTP1 유전자 다형성 사이에는 유의한 관련성이 관찰되지 않았다. 또한 IL-1 와 GSTP1 유전자 다형성 분포는 환자군과 대조군 사이에 유의한 차이를 보이지 않았다. 식이 습관과 음주 흡연 등의 변수와 위암 조직의 E-cadherin 유전자 촉진자의 과메틸화 여부와의 관련성 검정에서 돼지고기, 족발, 돈까스 등의 돼지고기류가 보호효과를 보였고 김치찌개, 매운 김치, 쑥은 위험요인으로 나타났다. 결론: 본 연구 결과 IL-1 와 GSTP1 유전자 다형성과 위암 조직의 E-cadherin 유전자 촉진자 과메틸화 사이에는 유의한 관련성을 볼 수 없었지만, E-cadherin 유전자 촉진자의 과메틸화와 식이 항목 사이에는 유의한 관련성을 관찰하였다. 이러한 결과들은 IL-1 나 GSTP1 보다는, 식이 요인 등의 생활습관이 E-cadherin 유전자 촉진자 과메틸화에 영향을 끼쳐 위암의 진행에 중요한 역할로 작용함을 시사한다. Purpose: Gastric cancer is the most common cancer in Korea. Hypermethylation of E-cadherin gene promoter is found in more than 50% of human gastric cancer tissues, and has been reported to be associated with the decreased expression of E-cadherin. The possibility of invasiveness and metastasis of gastric cancer increases in cases with the decreased expression of E-cadherin. The aim of this study is to investigate the effects of diet and genetic polymorphisms of IL-1β and GSTP1, and their interactions on the hypermethylation of E-cadherin gene promoter in gastric cancer tissues. Materials and Methods: One hundred and ten gastric cancer patients, and 220 age-and sex-matched controls were enrolled in this study. Direct interview using a semi-quantitative food frequency questionnaire (FFQ) was performed to get informations on the level of exposure to various diet. PCR-RFLP methods were used for the genotyping of IL-1β and GSTP1, and the methylation-specific PCR was applied to check hypermethylation of E-cadherin gene promoter in stomach cancer tissues. Results: Hypermethylation of E-cadherin gene promoter was detected in 40.0% of gastric cancer tissues. Pork, pettitoes, and pork cutlet were protective factors, whereas kimchi, kimchi stew, and mugwort were risk factors for the hypermethylation of E-cadherin gene promoter· in stomach cancer tissues. However, the hypermethylation of E-cadherin gene promoter was not associated with the genetic polymorphisms of IL-1β or GSTP1. Conclusion: These results suggest that the hypermethylation of E-cadherin promoter is associated with dietary factors but not with the genetic polymorphisms of IL-1β and GSTP1, and that progression of gastric cancer could be different according to the food intake pattern before the diagnosis of gastric cancer.