Signaling Pathways in Viral Related Pre-neoplastic Liver Disease and Hepatocellular Carcinoma
Hepatocellular carcinomas (HCC) demonstrates substantial genetic heterogeneity. Recent studies support the concept that such tumors exhibit cellular phenotypes that may correlate with tumor recurrence and overall survival. For example, the proliferative phenotype is characterize by the poor prognosis and is associated with growth factor signal transduction pathway activation whereas the “stem cell phenotype” portents activation of WNT/β-catenin signaling and generally has a better long term survival rate. Thus, most HCC tumors are associated with activation of the insulin/IGF-1/IRS-1/Ras/Raf/MAPK/Erk and WNT/Frizzled receptor/β-catenin signaling cascades which provide molecular targets for innovative therapy. Both pathways may be activated by genetic mutations (e.g. β-catenin), overexpression of upstream signaling components (e.g. WNTs, Frizzled receptors, IRS-1, etc.), or loss of regulatory proteins such as Ras or Raf kinase inhibitors. Evidence is presented that constitutive activation of the insulin/IGF-1/IRS-1/MAPK and WNT/β-catenin cascades are necessary and sufficient to transform normal liver to HCC in the context of hepatitis viral protein expression.
KeywordsHepatocellular carcinoma Signal transduction pathways Malignant transformation
This work was supported in part by NIH grants AA-02666, CA-35711, RR-015578, and Department of Medicine Development Research Award.
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