title: Reversible phospho-Smad3 signalling between tumour suppression and fibrocarcinogenesis in chronic hepatitis B infection.
abstract: Transforming growth factor (TGF)-β, type I receptor (TβRI) and c-Jun N-terminal kinases (JNK) phosphorylate Smad3 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 Smad3 phosphorylated isoforms before and after anti-viral therapy. To clarify the relationship between Smad3 phosphorylation and liver disease progression, we studied 10 random patients in each stage of HBV-related fibrotic liver disease (F1-4) and also 10 patients with HBV-associated HCC. To examine changes in phosphorylated Smad3 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 (Lamivudine 100 mg daily or Telbivudine 600 mg daily). Fibrosis stage, inflammatory activity and phosphorylated Smad3 positivity in the paired biopsy samples were compared. Hepatocytic pSmad3C signalling shifted to fibrocarcinogenic pSmad3L 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 pSmad3C signalling in hepatocytes, while eliminating prior fibrocarcinogenic pSmad3L signalling. Oral nucleoside analogue therapies can suppress fibrosis and reduce HCC incidence by successfully reversing phosphorylated Smad3 signalling; even liver disease progressed to cirrhosis in chronic hepatitis B patients.
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei, China; Intensive Care Unit, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, China.
authors.forename: Y-R
authors.initials: YR
authors.lastname: Deng
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
authors.forename: Q L
authors.initials: QL
authors.lastname: Jin
authors.forename: M
authors.initials: M
authors.lastname: Murata
authors.forename: T
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: K
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Y
authors.initials: Y
authors.lastname: Moritoki
authors.forename: J Q
authors.initials: JQ
authors.lastname: Niu
authors.forename: K
authors.initials: K
authors.lastname: Matsuzaki
authors.forename: Z-X
authors.initials: ZX
authors.lastname: Lian
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D004279:DNA, Viral / Q000097:blood; D018450:Disease Progression; D005260:Female; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000150:complications* / Q000188:drug therapy / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D019259:Lamivudine / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D008103:Liver Cirrhosis / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D008113:Liver Neoplasms / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism*; D000077712:Telbivudine; D013936:Thymidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D020033:Protein Isoforms; D051900:Smad3 Protein; D000077712:Telbivudine; D019259:Lamivudine; D013936:Thymidine
keywords: HBV; TGF-β; pSmadC; pSmadL