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Chromosomal instability, telomere shortening, and inactivation of p21(WAF1/CIP1) in dysplastic nodules of hepatitis B virus-associated multistep hepatocarcinogenesis

 Yoon Hee Lee  ;  Bong-Kyeong Oh  ;  Jeong Eun Yoo  ;  So-Mi Yoon  ;  Jinsub Choi  ;  Kyung Sik Kim  ;  Young Nyun Park 
 MODERN PATHOLOGY, Vol.22(8) : 1121-1131, 2009 
Journal Title
Issue Date
Adult ; Blotting, Southern ; Carcinoma, Hepatocellular/genetics* ; Carcinoma, Hepatocellular/pathology ; Carcinoma, Hepatocellular/virology ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Chromosomal Instability ; Cyclin-Dependent Kinase Inhibitor p21/genetics ; Cyclin-Dependent Kinase Inhibitor p21/metabolism* ; Female ; Gene Expression ; Gene Expression Profiling ; Gene Silencing ; Hepatitis B, Chronic/complications ; Hepatitis B, Chronic/genetics* ; Hepatitis B, Chronic/pathology ; Humans ; Immunohistochemistry ; Liver Neoplasms/genetics* ; Liver Neoplasms/pathology ; Liver Neoplasms/virology ; Male ; Micronuclei, Chromosome-Defective ; Middle Aged ; Precancerous Conditions/genetics* ; Precancerous Conditions/pathology ; Precancerous Conditions/virology ; Telomere/pathology*
dysplastic nodule ; hepatocellular carcinoma ; chromosomal instability ; p21WAF1/CIP1 ; telomere ; hepatitis B virus
Systemic analysis for chromosomal instability and inactivation of cell cycle checkpoints are scarce during hepatocarcinogenesis. We studied 24 patients with chronic B viral cirrhosis including 30 cirrhotic regenerative nodules, 35 low-grade dysplastic nodules, 15 high-grade dysplastic nodules, 7 dysplastic nodules with hepatocellular carcinoma foci, and 18 hepatocellular carcinomas. Eight normal livers were studied as the control group. Telomere length and micronuclei were detected by Southern blot and Feulgen-fast green dyeing technique, respectively, and p21(WAF1/CIP1) expression was studied by immunohistochemistry. Micronuclei >1 per 3000 hepatocytes were found in 17% of low-grade dysplastic nodules, 87% of high-grade dysplastic nodules, and 100% of high-grade dysplastic nodules with hepatocellular carcinoma foci and hepatocellular carcinomas in contrast to those of all normal livers, and 90% of cirrhosis showed no micronuclei. The micronuclei index showed a gradual increase during hepatocarcinogenesis and there was a significant increase between cirrhosis and low-grade dysplastic nodules, low-grade dysplastic nodules and high-grade dysplastic nodules, and high-grade dysplastic nodules and hepatocellular carcinomas. Telomere length showed a gradual shortening during hepatocarcinogenesis and a significant reduction was found in high-grade dysplastic nodules (P=0.024) and hepatocellular carcinomas (P=0.031) compared with normal and cirrhotic livers. The micronuclei index was correlated with telomere shortening (P=0.016). The p21(WAF1/CIP1) labeling index was significantly higher in cirrhosis than in normal livers (P=0.024) and markedly decreased in low-grade dysplastic nodules, high-grade dysplastic nodules, and hepatocellular carcinomas compared with cirrhosis (P<0.05). The p21(WAF1/CIP1) labeling index was associated with telomere length (P<0.001) but not micronuclei index. This study shows that telomere shortening, chromosomal instability, and inactivation of p21(WAF1/CIP1) checkpoint function occur in low-grade dysplastic nodules as well as in high-grade dysplastic nodules, and their cooperation is considered to be critical for malignant transformation during hepatitis B virus associated-multistep hepatocarcinogenesis
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Sik(김경식) ORCID logo https://orcid.org/0000-0001-9498-284X
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
Oh, Bong Kyeong(오봉경)
Yoo, Jeong Eun(유정은) ORCID logo https://orcid.org/0000-0001-9990-279X
Yoon, So Mi(윤소미)
Choi, Jin Sub(최진섭)
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