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Expression analysis of Hedgehog signaling components in human gallbladder cancer

Other Titles
 인체 담낭암에서의 Hedgehog 신호전달체계 물질의 발현에 관한 분석 
Authors
 김홍정 
Department
 Dept. of Internal Medicine (내과학교실) 
Issue Date
2008
Description
Dept. of Medicine/석사
Abstract
[한글] 배경: Hedgehog (Hh) 단백은 소화기암 발생에 필수적인 물질로, Hedgehog 신호 전달 체계의 혼란은 소화기암의 발생과 연관되며, 또한 최근 조혈 및 신경 줄기세포의 자가재생 능력의 조절과 연관되는 것으로 알려져 있는 Bmi-1은 Hedgehog 신호전달체계의 하류 전사 인자로써 작용한다. 이러한 과정들이 적절히 조절되지 못할 경우 암 발생의 중요한 원인이 되며, 이러한 사실들은 종양줄기세포를 표적으로 하는 치료적 접근의 합리적 가능성을 제시한다. 한편, 담낭암은 전세계적으로 드문 암이지만 그 발생률에 있어서 상당한 지역적 편차를 보이며 늦은 진단과 불만족스러운 치료성적으로 인해 예후가 좋지 않은 암으로 알려져 있어 새로운 치료방법의 개발이 절실히 요구되고 있다.목적 및 방법: Shh, Patched-2, Gli-1 및 Bmi-1을 포함하는 Hedgehog 신호전달체계가 인체 담낭암에서 어떤 역할을 하는지 알아보기 위하여, 2000년 1월부터 2006년 6월까지 신촌 세브란스 병원에서 담낭암으로 수술적 절제를 받은 환자로부터 얻은 담낭암 조직을 사용하여 면역화학염색 및 역전사효소 중합 연쇄반응을 시행하여 암의 분화도와 병기 등에 따른 차이를 평가하였다.결과: 총 59명의 환자 중에서 19명(32.2%)은 남성이었고 40명(67.8%)은 여성이었으며, 환자의 평균나이는 61(범위: 28-80)세였다. 각각 4쌍의 정상과 암 조직의 역전사효소 중합 연쇄반응 비교에서, 정상조직에 비해 담낭암 조직에서 Shh, Ptc-2, Gli-1 및 Bmi-1의 발현이 상대적으로 증가되어 있었으며 (Shh, 100%(4/4)., Ptc-2, Gli-1, Bmi-1, 75%(3/4)), 면역화학 염색에서는 Shh, Ptc-2, Gli-1과 Bmi-1에 대하여 각각 77.0 % (47/59), 80.4% (49/59), 77.0% (47/59) ,71.2% (42/59)의 환자에서 양성반응을 보였다. 낮은 병기일수록 강하게 염색되는 경향을 보였지만 (Shh p = 0.002., Bmi-1 and Ptc-2 p < 0.001., Gli-1 p = 0.001)., 담낭암의 분화도와 면역염색 정도간에 통계적 유의성은 없었다 (shh p = 0.108., Bmi-1 p=0.689., Ptc-2 p= 0.804., Gli-1 p = 0.613). 또한, Shh, Ptc-2, Gli-1 및 Bmi-1 모두 염색강도가 높을수록 더 긴 생존기간을 갖는 경향을 보였지만 Bmi-1만이 통계적으로 의미 있는 연관성을 보였다 (Shh p = 0.276., Bmi-1 p = 0.025., Ptc-2 p = 0.626., Gli-1 p = 0.574).결론: Hedgehog 신호전달체계와 Bmi-1은 인체 담낭암의 발현에 관여하고, 특히 Bmi-1은 예후와 강한 연관성을 보이지만, 암이 진행됨에 따라 인체 담낭암에서 이들의 역할은 점차 감소한다.
[영문] Background: Although gall bladder (GB) cancer is not a common neoplasm, it shows significant geographic variation in incidence. GB cancer is often diagnosed in advanced stage, obviating curative resection. In advanced stage GB cancers are not amenable to radiotherapy or chemotherapy. It is necessary, therefore, to elucidate molecular mechanism leading to cancer in order to develop effective treatment methods.Hedgehog (Hh) protein is an essential molecule for normal development of the gastrointestinal tract and the maintenance of the stem cell population, and disruption of Hh signaling is linked to various gastrointestinal tumors. Bmi-1, which is a member of polycomb gene, has recently been identified to play a role in the regulation of stem cell self-renewal and function as a downstream target of the Hh pathway. Deregulation of these processes during carcinogenesis may result in derangement in a stem cell compartment, a key event in carcinogenesis. Strategies aimed at inhibiting these pathways represent a rational therapeutic approach to target cancer stem cells.AIMS & METHODS: We performed Hh immunohistochemical staining (IHC) and reverse transcription-polymerase chain reaction (RT-PCR) to investigate the role of Hh signaling and Bmi-1 in human GB cancers. We also analyzed the change of expressions according to tumor stage and degree of differentiation. The GB cancer samples were obtained from patients who underwent radical surgery for GB cancer at the Severance hospital from January 2000 through June 2006. Immunohistochemical staining was carried out using formalin-fixed paraffin section and RT-PCR using fresh frozen tissue for the Hh signaling components (Shh, Ptc-2, Gli-1) and Bmi-1.RESULTS: Among the total of 59 patients, 19(32.2%) were male and 40(67.8%) were female. Mean age was 61(range: 28-80) years. On RT-PCR, the Ptc-2, Gli-1, and Bmi-1 mRNA levels were increased in human gallbladder cancers compared to non-tumorous tissue. On immunohistochemical staining, 77.0 % (47 of 59), 80.4% (49 of 59), 77.0% (47 of 59), and 71.2% (42 of 59) of the GB cancers were positive for Shh, Ptc-2, Gli-1, and Bmi-1, respectively. The expressions of Shh, Bmi-1, Ptc-2, and Gli-1 (Shh p = 0.002; Bmi-1 and Ptc-2 p<0.001; Gli-1 p = 0.001) was, however, inversely correlated with tumor stage, showing more robust expression in tumors with earlier stage.There was no difference in the levels of expression and the degrees of histologic differentiation of tumors. (Shh p = 0.108; Bmi-1 p = 0.689; Ptc-2 p = 0.804; Gli-1 p = 0.613). Strong expression of Bmi-1 gene was associated with longer survival (shh p = 0.276; Bmi-1 p = 0.025; Ptc-2 p = 0.626; Gli-1 p = 0.574).CONCLUSION: The results suggest that the Hh signaling pathway and Bmi-1 may play a role in the initiation of GB carcinogenesis. As cancers progress, they become less dependent on the Hh signaling and Bmi-1.
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 2. Thesis
Yonsei Authors
Kim, Hong Jeoung(김홍정)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/123947
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