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Ubiquitous activation of Ras and Jak/Stat pathways in human HCC.

Diego F Calvisi1, Sara Ladu, Alexis Gorden

  • 1Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4262, USA.

Gastroenterology
|April 19, 2006

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View abstract on PubMed

Summary

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  • Biomedical And Clinical Sciences
  • Oncology And Carcinogenesis
  • Predictive And Prognostic Markers
  • Ubiquitous Activation Of Ras And Jak/stat Pathways In Human Hcc.
    • This summary is machine-generated.

    Ras and Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathways are activated in human hepatocellular carcinoma (HCC). Inhibitors of these pathways, combined with demethylating agents, show therapeutic potential for liver cancer.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Cancer Pathogenesis

    Background:

    • Molecular pathogenesis of human hepatocellular carcinoma (HCC) is not fully understood.
    • Investigates the role of Ras and Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathways in HCC.

    Purpose of the Study:

    • To define the role of Ras and Jak/Stat pathways in human HCC.
    • To assess the therapeutic potential of targeting these pathways.

    Main Methods:

    • Assessed promoter and genomic status of Ras and Jak/Stat inhibitors in 80 HCCs.
    • Determined pathway activation using DNA sequencing, Western blot, and immunoprecipitation.
    • Evaluated pathway suppression effects on HCC cell line viability and apoptosis.

    Main Results:

    • Enhanced Ras and Jak/Stat pathway activation observed in all HCCs compared to normal liver.
    • Suppression of Ras (RASSF1A, NORE1A) and Jak/Stat (CIS, SOCS1/2/3, SHP1) inhibitors correlated with pathway activation.
    • Aberrant methylation of NORE1A and SOCS3 promoters linked to poor HCC survival.
    • Combined Ras/Jak/Stat inhibitors and demethylating agent induced apoptosis in HCC cell lines.

    Conclusions:

    • Ras and Jak/Stat pathways are ubiquitously activated in human HCC.
    • Ras and Jak/Stat inhibitors show potential as a therapeutic strategy for liver cancer.
    • Demethylating agents may enhance therapeutic efficacy in combination treatments.

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