Telomerase activity and telomere length in hepatocellular carcinoma and chronic liver disease

Kojima, Hiroshige; Yokosuka, Osamu; Imazeki, Fumio; Saisho, Hiromitsu; Omata, Masao

doi:10.1053/gast.1997.v112.pm9024303

Cited by 149 publications

(101 citation statements)

References 5 publications

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“…(1) sequential development of hepatocyte overproliferation-dysplasia-HCC; (2) overexpression of c-myc oncogene in the early premalignant steps (Zhang et al, 1990); (3) frequent reactivation of insulin-growth-factor II in HCCs (Liu et al, 1997); (4) frequent mutations of b-catenin gene in HCCs (De La Coste et al, 1998) and (5) frequent upregulation of telomerase in HCCs (Kojima et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Long-term high-dose interferon-α therapy delays Hepadnavirus-related hepatocarcinogenesis in X/myc transgenic mice

et al. 2003

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The role of interferon-a (IFN-a) remains unclear in prevention of virus-induced hepatocellular carcinoma in humans. We have investigated it herewith in the X/myc transgenic mouse model of Hepadnavirus-related hepatocarcinogenesis because of upregulation of c-myc oncogene in the liver. We have demonstrated that IFN-a can downregulate dose-dependently hepatocyte proliferation and c-myc overexpression at early premalignant stages, while it does not affect either hepatocyte apoptosis or telomerase activity at these steps. However, continuous and long-term administration of IFN-a dose-dependently delays tumor onset in dysplastic livers and increases overall survival of animals, more efficiently whether started before the onset of dysplasia. The present study therefore highlights that early preventive administration of IFN-a can slow down evolution towards hepatocellular carcinoma via repression of c-myc and hepatocyte proliferation at premalignant steps in experimental cmyc-induced hepatocarcinogenesis. However, the transient effect observed in this study emphasizes a need to clarify the possible mechanisms of acquired resistance and subsequent therapeutic escape. Our experimental model may be a pertinent tool to explore antioncogenic properties of IFN-a in human cirrhotic livers showing c-myc upregulation.

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Section: Discussionmentioning

confidence: 99%

Long-term high-dose interferon-α therapy delays Hepadnavirus-related hepatocarcinogenesis in X/myc transgenic mice

et al. 2003

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“…In a number of malignant tumors such as hepatocellular carcinoma, colon carcinoma, cervical carcinoma or certain leukemia, the progression of disease has been reported to clearly correlate with the extent of telomerase activity (Nakayama et al, 1998;Kojima et al, 1997;Nouso et al, 1996;Kitamoto and Ide, 1999;Kolquist et al, 1998). Therefore, it would be important to investigate whether the progression of a malignant disease correlates with the amount of hTERT auto-antibodies.…”

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confidence: 99%

Identification of serum anti-human telomerase reverse transcriptase (hTERT) auto-antibodies during progression to hepatocellular carcinoma

et al. 2002

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“…8 Although this variation should be normalized before comparison of telomere length among patients, all previous reports describing telomere alteration in chronic liver diseases were unfortunately evaluated without any standardization. [9][10][11][12] These technical limitations inherent in the complexity of TRF make it difficult to analyze telomere dynamics using clinical materials, especially in the case that only a small specimen is available.…”

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confidence: 99%

Reduction of telomeric repeats as a possible predictor for development of hepatocellular carcinoma: Convenient evaluation by slot-blot analysis

et al. 1999

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Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world, and hepatitis B and C viruses are the main causative agents for high incidence of HCC. 1 Although the mechanisms underlying HCC development have been widely investigated from both points of direct and indirect effects of the viruses, 2 they are still open to debate. Whatever the mechanisms involved, these viral infections are correlated with a slow, long-lasting disease that is a definite risk for neoplastic degeneration.Telomeres are composed of tandem arrays of a short DNA sequence, d(TTAGGG)n in vertebrates, and associated proteins. They are essential genetic elements and stabilize the natural ends of linear eukaryotic chromosomes. 3 The endreplication problem, the inability of DNA polymerases to completely replicate the end of a DNA duplex, 4 results in telomere shortening in proportion to cell replication. 5 Because severity of persistent hepatocellular degeneration might indicate a risk for HCC development, an extent of telomere erosion has a possibility to be a predictor for HCC development in the liver under chronic inflammation.The standard and currently most reliable method for evaluating telomere length uses Southern analysis of terminal restriction fragment (TRF) lengths. 6 TRFs, however, contain DNA other than uniform telomeric repeats, 7 and the analysis requires several micrograms of high-molecular-weight genomic DNAs. In addition, telomere length varies among individuals prior to replicative histories. 8 Although this variation should be normalized before comparison of telomere length among patients, all previous reports describing telomere alteration in chronic liver diseases were unfortunately evaluated without any standardization. 9-12 These technical limitations inherent in the complexity of TRF make it difficult to analyze telomere dynamics using clinical materials, especially in the case that only a small specimen is available.In this study, we first evaluated reliability and reproducibility of a slot-blot analysis to detect alteration of telomeric repeats content. Next, we determined the content in various liver tissues. For comparison of the content in the liver with respect to chronic inflammation, we standardized the content

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Telomerase activity and telomere length in hepatocellular carcinoma and chronic liver disease

Cited by 149 publications

References 5 publications

Long-term high-dose interferon-α therapy delays Hepadnavirus-related hepatocarcinogenesis in X/myc transgenic mice

Long-term high-dose interferon-α therapy delays Hepadnavirus-related hepatocarcinogenesis in X/myc transgenic mice

Identification of serum anti-human telomerase reverse transcriptase (hTERT) auto-antibodies during progression to hepatocellular carcinoma

Reduction of telomeric repeats as a possible predictor for development of hepatocellular carcinoma: Convenient evaluation by slot-blot analysis

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