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

Abstract

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 41 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 highgrade 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 ¼ 0.024) and hepatocellular carcinomas (P ¼ 0.031) compared with normal and cirrhotic livers. The micronuclei index was correlated with telomere shortening (P ¼ 0.016). The p21 WAF1/CIP1 labeling index was significantly higher in cirrhosis than in normal livers (P ¼ 0.024) and markedly decreased in low-grade dysplastic nodules, high-grade dysplastic nodules, and hepatocellular carcinomas compared with cirrhosis (Po0.05). The p21 WAF1/CIP1 labeling index was associated with telomere length (Po0.001) 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.

hSSB1 binds and protects p21 from ubiquitin-mediated degradation and positively correlates with p21 in human hepatocellular carcinomas

“…Both hSSB1 and p21 were mainly located in the nuclei of the cancer cells and were highly expressed in the HCC tissues (Figure 6a). This result was consistent with the majority of previous studies showing that the tumor cells of HCC exhibited positive nuclear staining of p21 (Qin et al, 1998;SchonigerHekele et al, 2005;Kao et al, 2007;Lee et al, 2009). However, some reports have showed cytoplasmic p21 staining in HCC (Tanaka et al, 2002;Lee and Helfman, 2004;Shiraki and Wagayama, 2006), and we also observed a weak cytoplasmic p21 staining in three cases (3%) of HCC tissues that were excluded in our statistical analyses in this report.…”

Ageing, telomeres, senescence, and liver injury

“…Further, they demonstrated declining telomere lengths with neoplastic hepatocytes having the shortest telomere length. Lee et al have extended these finding in HBVassociated carcinogenesis identifying an increase in micronuclei formation, p21 inactivation and reduction in telomere length from low grade dysplastic nodules to high grade dysplastic nodules to HCC [93].…”

Emerin Expression in Well Differentiated Epithelial Lesions of Thyroid: Implications in Papillary Thyroid Carcinoma Diagnosis and Predicting Malignant Behavior

“…Results of these studies indicate that histopathological or cytological examination of NPs may be used as additional biomarkers in cancer screening [28,27].…”