Telomere shortening and telomerase reactivation in dysplastic nodules of human hepatocarcinogenesis

Oh, Bong Kyeong; Chae, Kwang Jo; Park, Chan-Il; Kim, Kyung Sik; Lee, Woo Jung; Han, Kwang Hyub; Park, Young Nyun

doi:10.1016/s0168-8278(03)00395-7

Cited by 67 publications

(54 citation statements)

References 21 publications

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“…10 TL was measured from 2 mg HinfI-digested DNA. Hybridization was carried out with a 3 0 -end DIG-labeled d(TTAGGG) 4 (Roche Molecular Biochemicals, Mannheim, Germany) at 371C overnight.…”

Section: Materials and Methods Materials And Histopathological Examinmentioning

confidence: 99%

“…10 All samples were assayed with 0.2 mg lysate, providing activity in the linear range. Assays were duplicated; the mean values were taken as the TA of the samples.…”

Section: Materials and Methods Materials And Histopathological Examinmentioning

confidence: 99%

“…8,9 Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide, accounting for the highest number of adult malignancies in areas endemic for hepatitis B virus (HBV). Telomere shortening is an early event in multistep hepatocarcinogenesis, occurring in preneoplastic lesions of dysplastic nodules 10,11 and shortened telomeres have been reported to induce chromosomal instability in hepatocytes, especially important in HBV-related hepatocarcinogenesis. 12,13 However, the roles of telomere dysfunction and telomerase parameters in the progression of human HCCs have not been systematically analyzed.…”

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confidence: 99%

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High telomerase activity and long telomeres in advanced hepatocellular carcinomas with poor prognosis

Kim

Park

et al. 2008

Laboratory Investigation

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Telomerase reactivation and telomere maintenance are crucial in carcinogenesis and tumor progression. In this study, the relationships between telomere parameters, chromosomal instability and clinicopathological features were evaluated in hepatocellular carcinomas (HCCs). Telomere length (TL), telomerase activity (TA) and human telomerase reverse transcriptase (hTERT) mRNA levels were measured in 49 hepatitis B virus (HBV)-related HCCs and corresponding non-tumorous tissues. The results were compared with clinicopathological data, including differentiation, multipolar mitosis (MM), anaphase bridge, immunohistochemical stain results for cytokeratin 19 (CK19) and patient outcome. TL of HCCs ranged from 4.7 to 13.1 kb, and 44.4% of HCCs showed telomere lengthening. hTERT mRNA levels and TA were closely related (P ¼ 0.008), and were significantly higher in HCCs than non-tumorous tissues. TL was significantly higher in HCCs with strong TA (P ¼ 0.048), high hTERT mRNA levels (P ¼ 0.001) and poor differentiation (P ¼ 0.041). Frequent MM was associated with poor differentiation (P ¼ 0.007) and advanced stage (Po0.001). TA was positively correlated with MM, anaphase bridges and advanced stage (P ¼ 0.019, P ¼ 0.017 and P ¼ 0.029). Thirteen (28.3%) HCCs were CK19 þ and demonstrated longer telomeres than CK19À HCCs (P ¼ 0.046). Overall survival was poor in HCCs with MM 40.4 per field (P ¼ 0.016), high TA (P ¼ 0.009) and high TL ratio (HCC/non-HCC) 40.8 (P ¼ 0.044). Our results show that long telomeres, high TA and high mitotic instability are poor prognostic markers for HBV-related HCCs and their close association suggests that telomere maintenance may be important for the progression of HCCs with high chromosomal instability to more aggressive ones.

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“…10 TL was measured from 2 mg HinfI-digested DNA. Hybridization was carried out with a 3 0 -end DIG-labeled d(TTAGGG) 4 (Roche Molecular Biochemicals, Mannheim, Germany) at 371C overnight.…”

Section: Materials and Methods Materials And Histopathological Examinmentioning

confidence: 99%

“…10 All samples were assayed with 0.2 mg lysate, providing activity in the linear range. Assays were duplicated; the mean values were taken as the TA of the samples.…”

Section: Materials and Methods Materials And Histopathological Examinmentioning

confidence: 99%

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confidence: 99%

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High telomerase activity and long telomeres in advanced hepatocellular carcinomas with poor prognosis

Kim

Park

et al. 2008

Laboratory Investigation

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“…[32][33][34] The average telomere length of HCC has been significantly and consistently shorter than that of adjacent chronic hepatitis or cirrhosis tissue. 47 Plentz et al demonstrated a correlation between telomere shortening and aneuploidy in human HCC.…”

Section: Discussionmentioning

confidence: 99%

“…Telomere shortening has been documented in patients with chronic liver disease, [32][33][34] suggesting that senescence and increased susceptibility to mutagenesis may occur as a result of continued injury and regeneration of hepatocytes. HBx was demonstrated to up-regulate the expression of human TERT [35][36][37] ; however, these reports were mostly descriptive studies.…”

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confidence: 99%

X protein of hepatitis B virus functions as a transcriptional corepressor on the human telomerase promoter†

Su¹,

Lai

Lan

et al. 2007

Hepatology

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The X protein of hepatitis B virus (HBx) is essential for transactivation of hepatitis B viral and host cellular genes. It has been specifically implicated in the development of hepatocellular carcinoma; however, the molecular mechanism remains unknown. Telomeres, the DNA-protein complexes at the ends of eukaryotic chromosomes, protect chromosomes from degradation at the terminal regions, fusion with a broken DNA end, and inappropriate recombination. The shortening of telomeres that occurs during hepatocellular carcinogenesis has been well studied. In the present study, we isolated an HBx isoform that resulted in telomere shortening in hepatoma cell lines. We found that this HBx isoform down-regulated the expression of human telomerase by transcriptionally repressing its promoter. To further determine the molecular mechanism, we examined human telomerase promoter and identified myc-associated zinc finger protein (MAZ) as a transcriptional repressor of the promoter. We found that the HBx isoform achieved transcriptional suppression of human telomerase by enhancing MAZ binding to its consensus sequence in the promoter through physical association with MAZ. Conclusion: The data suggest that HBx can induce telomere shortening by acting as a transcriptional corepressor of MAZ on the human telomerase promoter. (HEPATOLOGY 2007;46:402-413.)

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Telomeres and Aging, Cancer, and Hepatic Fibrosis

et al. 2009

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Telomere shortening and telomerase reactivation in dysplastic nodules of human hepatocarcinogenesis

Cited by 67 publications

References 21 publications

High telomerase activity and long telomeres in advanced hepatocellular carcinomas with poor prognosis

High telomerase activity and long telomeres in advanced hepatocellular carcinomas with poor prognosis

X protein of hepatitis B virus functions as a transcriptional corepressor on the human telomerase promoter†

Telomeres and Aging, Cancer, and Hepatic Fibrosis

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