Chromosomal instability, telomere shortening, and inactivation of p21WAF1/CIP1 in dysplastic nodules of hepatitis B virus-associated multistep hepatocarcinogenesis

被引：33

作者：

Lee, Yoon Hee ^{[1
,2
]}

Oh, Bong-Kyeong ^{[3
,4
]}

Yoo, Jeong Eun ^{[1
]}

Yoon, So-Mi ^{[1
]}

Choi, Jinsub ^{[5
]}

Kim, Kyung Sik ^{[5
]}

Park, Young Nyun ^{[1
]}

机构：

[1] Yonsei Univ, Coll Med, Dept Pathol,Ctr Chron Metab Dis, Brain Korea Project Med Sci 21,Inst Gastroenterol, Seoul 120752, South Korea

[2] CHA Univ, CHA Gangnam Med Ctr, Dept Pathol, Seoul, South Korea

[3] Konkuk Univ, Bio Mol Informat Ctr, Seoul, South Korea

[4] Yonsei Univ, Coll Med, Canc Metastasis Res Ctr, Seoul 120752, South Korea

[5] Yonsei Univ, Coll Med, Dept Surg, Seoul 120752, South Korea

来源：

MODERN PATHOLOGY | 2009年 / 22卷 / 08期

关键词：

dysplastic nodule; hepatocellular carcinoma; chromosomal instability; p21(WAF1/CIP1); telomere; hepatitis B virus; HUMAN CIRRHOTIC LIVERS; HEPATOCELLULAR-CARCINOMA; DNA-DAMAGE; MICRONUCLEI FORMATION; GENE; TUMORIGENESIS; SENESCENCE; GRADE; CELLS;

D O I：

10.1038/modpathol.2009.76

中图分类号：

R36 [病理学];

学科分类号：

100104 ;

摘要：

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. Modern Pathology (2009) 22, 1121-1131; doi: 10.1038/modpathol.2009.76; published online 22 May 2009

引用

页码：1121 / 1131

页数：11

共 33 条

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