Reversible phospho‐ S mad3 signalling between tumour suppression and fibrocarcinogenesis in chronic hepatitis B infection

Summary Transforming growth factor ( TGF )‐β, type I receptor ( TβRI ) and c‐ J un N ‐terminal kinases ( JNK ) phosphorylate S mad3 differentially to create 2 isoforms phosphorylated (p) at the COOH ‐terminus ( C ) or at the linker region ( L ) and regulate hepatocytic fibrocarcinogenesis. This study aimed to compare the differences between how hepatitis B virus ( HBV ) infection affected hepatocytic S mad3 phosphorylated isoforms before and after anti‐viral therapy. To clarify the relationship between S mad3 phosphorylation and liver disease progression, we studied 10 random patients in each stage of HBV ‐related fibrotic liver disease ( F 1–4) and also 10 patients with HBV ‐associated HCC . To examine changes in phosphorylated S mad3 signalling before and after anti‐ HBV therapies, we chose 27 patients with chronic hepatitis B who underwent baseline and follow‐up biopsies at 52 weeks from the start of nucleoside analogue treatments ( L amivudine 100 mg daily or T elbivudine 600 mg daily). Fibrosis stage, inflammatory activity and phosphorylated Smad3 positivity in the paired biopsy samples were compared. Hepatocytic p S mad3 C signalling shifted to fibrocarcinogenic p S mad3 L signalling as the livers progressed from chronic hepatitis B infection to HCC . After nucleoside analogue treatment, serum alanine aminotransferase ( ALT ) and HBV ‐ DNA levels in 27 patients with HBV ‐related chronic liver diseases were decreased dramatically. Decrease in HBV ‐ DNA restored p S mad3 C signalling in hepatocytes, while eliminating prior fibrocarcinogenic p S mad3 L signalling. Oral nucleoside analogue therapies can suppress fibrosis and reduce HCC incidence by successfully reversing phosphorylated S mad3 signalling; even liver disease progressed to cirrhosis in chronic hepatitis B patients.