Insights into hepatic fibrogenesis and carcinogenesis (fibro-carcinogenesis) have come to light in recent analyses of transforming growth factor (TGF)-b signaling directed by multiple phosphorylated (phospho-) isoforms of Smad mediators. Clinical observations suggest synergy between persistent hepatitis viral infection and chronic inflammation during human fibro-carcinogenesis. Considering basic research together with clinical outcomes, we first outline how hepatitis viruses and chronic inflammation additively promote hepatic fibro-carcinogenesis in hepatitis virus-related liver diseases, focusing on perturbation of Smad phospho-isoform signaling. We then consider the reversibility of Smad phospho-isoform signaling from fibro-carcinogenesis to tumor suppression after anti-viral therapies. Recent progress in Smad phospho-isoform signaling should permit the use of Smad phosphorylation as a prognostic indicator and as a biomarker in assessing effectiveness of interventions against human hepatic fibro-carcinogenesis.
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