TGF-β-miR-34a-CCL22 Signaling-Induced Treg Cell Recruitment Promotes Venous Metastases of HBV-positive Hepatocellular Carcinoma

Cancer Cell. 2012 Sep 11;22(3):291-303. doi: 10.1016/j.ccr.2012.07.023.

Abstract

Portal vein tumor thrombus (PVTT) is strongly correlated to a poor prognosis for patients with hepatocellular carcinoma (HCC). In this study, we uncovered a causative link between hepatitis B virus (HBV) infection and development of PVTT. Mechanistically, elevated TGF-β activity, associated with the persistent presence of HBV in the liver tissue, suppresses the expression of microRNA-34a, leading to enhanced production of chemokine CCL22, which recruits regulatory T (Treg) cells to facilitate immune escape. These findings strongly suggest that HBV infection and activity of the TGF-β-miR-34a-CCL22 axis serve as potent etiological factors to predispose HCC patients for the development of PVTT, possibly through the creation of an immune-subversive microenvironment to favor colonization of disseminated HCC cells in the portal venous system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / secondary*
  • Carcinoma, Hepatocellular / virology
  • Cell Line, Tumor
  • Chemokine CCL22 / metabolism*
  • Female
  • Hepatitis B / complications*
  • Hepatitis B virus / metabolism
  • Humans
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms / immunology
  • Liver Neoplasms / pathology*
  • Liver Neoplasms / virology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • MicroRNAs / biosynthesis
  • MicroRNAs / metabolism*
  • Middle Aged
  • Neoplasm Metastasis
  • Portal Vein*
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology*
  • Transforming Growth Factor beta / metabolism*
  • Tumor Microenvironment

Substances

  • CCL22 protein, human
  • Chemokine CCL22
  • MIRN34 microRNA, human
  • MicroRNAs
  • Transforming Growth Factor beta