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Large liver cell dysplasia in hepatitis B virus-related chronic liver disease

Other Titles
 만성 B형 간염 바이러스성 간질환에서 큰 간세포 이형성의 의의 
Authors
 김혜령 
Department
 Dept. of Pathology (병리학교실) 
Issue Date
2008
Description
Dept. of Medicine/박사
Abstract
[한글]

간세포 이형성은 육안적으로 확인할 수 없는 1mm 이하의 크기의 병변으로 뚜렷한 결절을 형성하지 않으며 작은 간세포 이형성 (small liver cell dysplasia; SLCD)와 큰 간세포 이형성 (large liver cell dysplasia; LLCD)으로 분류할 수 있다. SLCD는 전암병변으로서 어느 정도 개념이 정립되어 있으나, LLCD의 경우는 단순한 반응성 변화인지, 또는 간세포암종 발생과 밀접한 연관이 있는 전암병변인지 아직 의견의 일치가 없다. 본 연구에서는 LLCD의 유전생물학적 특성에 대하여 살펴보고 LLCD의 전암병변으로서의 의의를 밝히는 것이 목적이다.

외과적으로 절제한 만성 B형 간염 바이러스성 간경변 34 증례를 대상으로 연구를 시행하였으며 LLCD 31증례, SLCD 19증례 및 HCC 21증례가 포함되었다. 세포주기조절인자인 p21, p27, p16, Tp53, DNA 손상 표지자인 γ-H2AX에 대한 면역조직화학염색을 시행하였고, 세포역동성을 알아보기 위하여 세포증식능 표지자 PCNA와 Ki-67 발현율 및 세포고사의 빈도를 측정하였다. 또한 Feulgen 방법으로 미세핵의 빈도를 구하여 염색체 불안정성의 정도를 살펴보았고, 정량적인 형광제자리부합화 방법으로 각 병변세포의 텔로미어 길이를 측정하였으며, senescence-associated β-galactosidase (SA-β-Gal) 염색으로 세포노화 여부를 판단하였다.

이형성이 없는 간세포, LLCD, SLCD 및 간세포암종의 순서로 세포주기조절인자 (p21, p27, p16, p53)의 소실의 정도가 높았고, γ-H2AX 병소 및 미세핵의 빈도도 점점 증가하는 양상을 보였다. PCNA, Ki-67 및 TUNEL labeling index로 알아본 net cellular gain도 이형성이 없는 간세포, LLCD, SLCD, 간세포암종 순으로 높아졌으며, 텔로미어 길이는 점점 짧아졌고, SA-β-Gal 염색상 간경변에서는 노화된 세포가 많이 관찰되었으나, LLCD 및 SLCD에서는 관찰되지 않았다. 따라서 LLCD는 노화성 병변보다는 증식성 병변일 가능성이 더 높을 것으로 판단되며, 세포주기조절인자의 비활성화, 텔로미어 길이의 감소, DNA 손상 및 염색체 불안정성의 증가를 보이는 병변으로 간암발생과 밀접한 연관이 있는 전암병변일 가능성을 본 연구에서 제시하고자 한다.





[영문]

Liver cell dysplasia or dysplastic foci are defined as microscopic lesions measuring less than 1mm in diameter which do not form circumscribed nodules, and are often found in chronic liver disease. These lesions have been classified into two types: large liver cell dysplasia (LLCD) and small liver cell dysplasia (SLCD). Although SLCD has been more or less established as a precursor to hepatocellular carcinoma (HCC), the significance of LLCD is still controversial - while some have favored a reactive/degenerative nature for the lesion, there is increasing evidence that it may actually be related to hepatocarcinogenesis. A comprehensive analysis of LLCD was performed in this study, evaluating the cell cycle dynamics, proliferation and apoptosis, DNA damage and senescence. The molecular features - including senescence, cell cycle checkpoint status, DNA damage and chromosomal instability - and cell dynamics of LLCD in HBV-related cirrhotic livers were explored to further characterize the nature of LLCD.

Thirty-four formalin-fixed specimens and 19 fresh frozen liver specimens were obtained from surgically resected cases of HBV-related cirrhosis and examined for the presence of LLCD, SLCD and HCC. The immunohistochemical expression of p21, p27, p16, Tp53, PCNA, Ki-67 and γ-H2AX, telomere lengths, apoptotic activity, micronuclei index and senescence-associated β-galactosidase (SA-β-Gal) activity were examined for each lesion.

The p21, p27 and p16 cell cycle checkpoint markers - which were expressed at low levels in normal hepatocytes - were activated in cirrhosis but were diminished gradually from LLCD through SLCD to HCC, along with an increase in Tp53 expression. Significant shortening of telomere length was seen in non-dysplastic hepatocytes compared to normal liver, and in LLCD compared to non-dysplastic hepatocytes. There was a general decrease in telomere length from non-dysplastic hepatocytes, LLCD, SLCD to HCC. The accumulation of γ-H2AX foci and the micronuclei index were extremely low in normal hepatocytes and there was a significant gradual increase from non-dysplastic hepatocytes, LLCD, SLCD to HCC. An increase in net cellular gain (high proliferative activity and low apoptotic index) from normal hepatocytes, non-dysplastic hepatocytes, LLCD, SLCD to HCC was seen. The SA-β-Gal activity was weaker and less frequent in LLCD compared to the periseptally located non-dysplastic hepatocytes.

The increase in net cellular gain and the weak SA-β-Gal activity in LLCD suggest that LLCD may represent a proliferative lesion rather than a population of terminally differentiated end-stage hepatocytes. The loss of cell cycle checkpoint markers in LLCD may allow clonal expansion of hepatocytes with dysfunctional, shortened telomeres, and accumulation of DNA damage and chromosomal instability.
Files in This Item:
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 3. Dissertation
Yonsei Authors
Kim, Hae Ryoung(김혜령)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/124179
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