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Aflatoxin B1이 사염화탄소에 의한 흰쥐 간손상시 초기성장반응유전자와 변형성장인자에 미치는 영향

Other Titles
 (The) effect of aflatoxin B1 on the expression of early response genes and transforming growth factor-a 
Authors
 홍순원 
Issue Date
1995
Description
의학과/박사
Abstract
[한글]

Aflatoxin B1은 aspergillus flavus가 만드는 진균성 독소로서 간세포암종(hepatocellular carcinoma, HCC)을 유발하는 요인 중의 하나로 지적되어 왔다. 그러나 aflatoxin B1 투여에 의한 분자생물학적 변화에 대하여 알려진 것이 거의 없기 때문에 이에 의한 HCC 발생 과정을 정확하게 이해하기가 어렵다. 그러므로 본 연구에서는 aflatoxin B1 투여시간의 초기 분자생물학적 변화를 검색하고, 그러한 변화들이 간의 재생과 HCC 발생에서 어떠한 역할을 하는지를 알아보고자 하였다. 이를 위하여 Sprague-Dawley계 흰쥐를 사염화탄소 (CCl^^4) 단독투여군, aflatoxin B1 단독투여군 및 aflatoxin B1과 CCl^^4, 병합투여군으로 나누었다. 계획된 시간에 도살한 다음 간을 대상으로 하여 bromodeoxyuridine (BrdU)-anti BrdU 면역조직화학검사와 apoptosis kit를 이용한 TUNEL assay로 각각 세포재생능 및 apoptosis를 검색하고, Western B1otting으로 초기성장반응 유전자 c-myc 및 c-fos와 α-변형성장인자 (transforming growth factor-α, TGF-α)의 발현을 검색하였으며,

그 결과를 요약하면 다음과 같다. BrdU 표지지수는 CCl^^4 단독투여군과 aflatoxin B1 및 CCl^^4, 병합투여군에서 모두 48시간에 가장 높았으며, 그 정도는 병합투여군에서 의의있게 낮았다. CCl^^4 단독투여군에서는 BrdU 표지세포가 주로 분화된 간세포인 반면 aflatoxin B1 병합투여군에서 보인 BrdU 표지세포는 대개 미분화세포였다. Apoptosis와 괴사는 CCl^^4 단독투여군과 aflatoxin B1 및 CCl^^4 병합투여군에서 모두 관찰되었으며, CCl^^4 단독투여군에서는 24시간에만 현저하게 증가한 반면 병합투여군에서는 12시간에 시작되어 48시간까지 지속적으로 증가하였다. c-myc은 CCl^^4 단독투여군에서는 1시간에 최고에 달하였다가 점차 소실된 반면 aflatoxin B1과 CCl^^4 병합투여군과 aflatoxinB1 단독투여군에서는 처음부터 전기간동안 강하게 발현되고 특히 병합투여군에서는 30분과 6시간에 최고치를 보였다. c-fos는 CCl^^4 단독투여군에서는 24시간에만 강하게 발현된 반면 aflatoxin B1과 CCl^^4 병합투여군에서는 처음부터 점차적으로 발현강도가 증가하여 전기간동안 지속하였고 특히 24시간에 최고치를 보였다. TGF-α는 모든 군에서 전기간동안 비슷한 정도로 발현하였다.

이상의 결과를 종합하면 aflatoxin B1과 CCl^^4를 병합투여할 경우 CCl^^4 단독투여시보다 c-myc이 강하게 그리고 지속적으로 발현되어 분화된 간세포의 사멸이 심하게 지속되며, 동시에 C-fos의 세포증식 신호전달이 오랫동안 지속함에 따라 불가피하게 미분화세포의 중식이 일어남을 암시하며, 따라서 aflatoxin B1에 의한 HCC 발생은 분화된 간세포보다는 미분화세포의 증식에 의한 것일 가능성이 높다고 생각된다.

[영문]

Aflatoxin B1, a fungal toxin produced by aspergillus flavus, has been known to be a possible hepatocarcinogen. But the molecular biologic changes which might occur following exposure to aflatoxin B1 is not known and thus the carcinogenesis not understood as yet. This study was performed to examine the expressions of c-myc, c-fos and TGF-α genes and to investigate the possible role of those molecular biologic changes in hepatic regeneration and development of hepatocellular carcinoma(HCC). Sprague-Dawley rats were divided into 3 groups: Carbon tetrachloride (CCl^^4) only administered group(Ⅰ), aflatoxin B1 only administered group(Ⅱ) and combined aflatoxin B1 and CCl^^4, administered group(Ⅲ). Animals were sacrificed at 0.5, 1, 2, 6, 12, 24, 48, and 72 hours after treatment. In addition to the examination of hematoxylin-eosin stained sections, hepatic

regeneration and apoptosis were analyzed quantitatively by

bromodeoxyuridine(BrdU)-anti BrdU immunohistochemistry and TUNEL assay utilizing apoptosis kit, respectively. The hepatic expressions of c-myc and c-fos were studied by Western blot and quantitiated by laser densitometer. The hepatic expression of transforming growth factor-α (TGF-α) was examined by immunohistochemistry and Western blot. The number of BrdU labelled cells and the degree of necrosis apoptosis were comparable among different groups. Liver of the group Ⅱ rats showed nearly normal histology without regeneration and necrosis

apoptosis. In groups Ⅰ and Ⅲ, was significantly marked in group Ⅰ than in group Ⅲ. Most BrdU labelled cells were mature hepatocytes in group Ⅰ, whereas in group Ⅲ, they appeared to be less mature. In group Ⅰ,apoptosis was increased at around 24 hours, but appealed in group Ⅲ as early as 12 hours and persisted through 48 hours after treatment. The expressions of c-myc and c-fos were also different between the experimental groups. The expression intensity of c-mycr in group Ⅰ was highest at 1 hour which decreased thereafter. In groups Ⅱ and Ⅲ, the expressions were much more intense than in group Ⅰ except for at 1 hour and the increased intensity persisted throughout the experiment. Group Ⅲ in particular showed peak

intensity at 30 minutes and 6 hours after treatment. In group Ⅰ, c-fos was strongly expressed only at 24 hours, but in group Ⅲ, there was a progressively increasing expression with peak intensity at 24 hour. TGF-α was expressed in similar intensities in all groups throughout the experiment. These results suggest

that aflatoxin B1 may evoke an intense and protracted expression of c-myc, provocating the CCl^^4 induced necrosis of hepatocytes, and a prolonged expression of c-fos, inducing persistent signaling for regeneration which in turn may activate immature cells to replicate.
Full Text
https://ymlib.yonsei.ac.kr/catalog/search/book-detail/?cid=CAT000000003112
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 3. Dissertation
Yonsei Authors
Hong, Soon Won(홍순원) ORCID logo https://orcid.org/0000-0002-0324-2414
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/118210
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