Activation of c-myc by woodchuck hepatitis virus insertion in hepatocellular carcinoma

Hsu, Ting-Yu; Möröy, Tarik; Etiemble, Jeanne; Louise, Anne; Trépo, C.; Tiollais, Pierre; Buendía, Marie-Annick

doi:10.1016/0092-8674(88)90221-8

Cited by 183 publications

(95 citation statements)

References 43 publications

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“…Activation of oncogenes caused by hepatitis virus integration has been well shown in the woodchuck animal model (Hsu et al, 1988;Fourel et al, 1990). The integration of HBV into genomic DNA is associated with chromosome changes in recipient cells Table 2 Appearing frequency of abnormal chromosomes in 22 karyotypes analysed (35th passage) Frequency 22 14 9 12 9 20 16 15 22 22 Chromosome +11 +12×2 -13 -14 -15 +16 +18 M4 M5 M6 Frequency 15 17 22 22 22 11 11 12 12 14 Chromosome +19 +20 -21×2 M 7 M 8 Frequency 9 12 22 15 17 *Appearing frequency of abnormal chromosomes exceeded 50% of karyotypes analysed.…”

Section: Discussionmentioning

confidence: 99%

New human hepatocellular carcinoma (HCC) cell line with highly metastatic potential (MHCC97) and its expressions of the factors associated with metastasis

et al. 1999

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Human hepatocellular carcinoma (HCC) is one of the most common types of tumour, especially in Asia and Africa (Anderson et al, 1992;Okuda, 1992;Parkin et al, 1993). HCC is characterized by extensive carcinoma cell infiltration and metastasis. Although advances have been made in liver cancer therapies, most cancer deaths still result from metastatic disease, so metastasis has been the greatest obstacle to successful tumour treatment. The poor understanding of the molecular mechanisms responsible for the disseminated metastasis, which would be partly due to the lack of ideal samples and models for study, has hindered the development of effective antimetastatic therapies. Although several reports of the establishment of HCC cell lines were available (Chen, 1963;Alexander et al, 1976;Dong et al, 1980), none have demonstrated prominent metastatic potential. The human cell line with a metastatic potential from primary tumour or metastatic lesions would permit metastatic mechanisms to be studied further. However, the cancer cells from the surgical samples or metastatic lesions can only be maintained in primary culture for a short time before cellular senescence occurs. The aim of this study was to establish a human HCC cell line with a metastatic potential. We successfully established a new HCC cell line with a highly metastatic potential derived from subcutaneous xenograft of a metastatic model of human HCC in nude mice (LCI-D20) (Sun et al, 1996) by improving the conventional method of establishing a cell line -alternating cell culture in vivo and growth in nude mice. In this paper the processes of establishing a new human HCC cell line MHCC97 and some characteristics, including observation of some factors associated with metastasis, are reported. MATERIALS AND METHODS Specimens and in vitro cultureSeventy-eight primary cultures were taken from subcutaneous or intrahepatic xenografts of LCI-D20 nude mouse models. The model was developed by orthotopic inoculation of an intact tumour tissue of an intrahepatic disseminated lesion from a 39-year-old Chinese male patient with HCC (Zhong-Shan Hospital, Shanghai Medical University). Abnormal alpha-fetoprotein (AFP) and HBsAg were found in serum from this patient. The LCI-D20 model represents 100% metastases to the lungs, lymph nodes and intrahepatic spreading (Sun, 1996). These xenografts were removed and used for primary culture in vitro by different culture methods (tissue fragments or single-cell Summary A new human hepatocellular carcinoma (HCC) cell line with a highly metastatic potential was established from subcutaneous xenograft of a metastatic model of human HCC in nude mice (LCI-D20) by means of alternating cell culture in vitro and growth in nude mice. The line, designated MHCC97, has been cultivated for 18 months and subcultured for more than 90 passages. The line was showed to be of human origin by karyotype analysis. The cells were either grown as compact colonies (in clusters) or as a monolayered sheet with about 31 h of population-doubling time, exhibited ty...

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Section: Discussionmentioning

confidence: 99%

New human hepatocellular carcinoma (HCC) cell line with highly metastatic potential (MHCC97) and its expressions of the factors associated with metastasis

et al. 1999

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“…The proto-oncogene c-myc stimulates a pattern of cellular gene expression by its regulatory elements and is involved in gene expression during cell growth and differentiation (Evan and Littlewood, 1993). It has been shown to be important in the process of hepatocarcinogenesis in woodchucks and transgenic mice (Hsu et al, 1988;Etiemble et al, 1994). However, its role in human hepatocarcinogenesis remains unclear.…”

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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“…Furthermore, the integration of woodchuck hepatitis virus (WHV), an animal virus resembling HBV, often occurs in c-Myc or N-Myc genes. Direct transforming activity of WHV/Myc integrants is thought to lead to the development of animal HCCs (Hsu et al, 1988;Fourel et al, 1990). Other reports describe genes with important roles in cell growth, such as retinoic acid receptor beta, cyclin A2, mevalonate kinase, sarco/endoplasmic reticulum calcium ATPase 1 and human minichromosome maintenance protein 8, undergoing deregulation by HBV insertion (for reviews, see Bre´chot et al, 2000;Paterlini-Bre´chot et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Hepatitis B virus-related insertional mutagenesis in chronic hepatitis B patients as an early drastic genetic change leading to hepatocarcinogenesis

et al. 2005

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Growing evidence demonstrates that hepatitis B virus (HBV) integration and resulting insertional mutagenesis play an important role in cell growth or maintenance in hepatocellular carcinomas (HCCs). To determine if HBV integration occurs and affects cellular genes at such a stage of infection, we analysed viral-host junctions in chronic hepatitis tissues without HCC using PCR amplification with primers specific to human Alu-repeat and HBV. We obtained 42 independent viral-host junctions from six patients examined and identified chromosomal locations for 20 of the 42 junctions. In six clones, each integration apparently affected a single gene. These six candidate genes included one known tumor suppressor gene, three human homologs of drosophila genes that are critical for organ development, one putative oncogene and one recently found chemokine. Our data, together with previously reported HBV integrants in HCCs, suggested preferential HBV integration into chromosome 3 (P ¼ 0.022). Our virus-tagging approach provided (a) firm evidence of HBV integration in hepatocytes at an early stage of chronic infection and (b) revealed cellular genes possibly affected by HBV integration and potentially involved in early steps of the process leading to carcinogenesis.

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Activation of c-myc by woodchuck hepatitis virus insertion in hepatocellular carcinoma

Cited by 183 publications

References 43 publications

New human hepatocellular carcinoma (HCC) cell line with highly metastatic potential (MHCC97) and its expressions of the factors associated with metastasis

New human hepatocellular carcinoma (HCC) cell line with highly metastatic potential (MHCC97) and its expressions of the factors associated with metastasis

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

Hepatitis B virus-related insertional mutagenesis in chronic hepatitis B patients as an early drastic genetic change leading to hepatocarcinogenesis

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