Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion

Nat Commun. 2018 Mar 28;9(1):1241. doi: 10.1038/s41467-018-03584-3.


A chronic viral or tumor microenvironment can push T cells to exhaustion by promoting coinhibitory ligand expression. However, how host factors control coinhibitory ligand expression and whether viral infection breaks this control during tumor progress is unknown. Here we show a close negative correlation between SALL4 or PD-L1 and miR-200c in tumors from 98 patients with HBV-related hepatocellular carcinoma. SALL4 or PD-L1 expression correlates negatively with miR-200c expression, and patients with lower levels of SALL4 or PD-L1 and higher miR-200c survive longer. Moreover, over-expression of miR-200c antagonizes HBV-mediated PD-L1 expression by targeting 3'-UTR of CD274 (encoding PD-L1) directly, and reverses antiviral CD8+ T cell exhaustion. MiR-200c transcription is inhibited by oncofetal protein SALL4, which is re-expressed through HBV-induced STAT3 activation in adulthood. We propose that an HBV-pSTAT3-SALL4-miR-200c axis regulates PD-L1. Therapeutic strategies to influence this axis might reverse virus-induced immune exhaustion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Antiviral Agents / therapeutic use
  • B7-H1 Antigen / metabolism*
  • CD8-Positive T-Lymphocytes / immunology*
  • Carcinoma, Hepatocellular / metabolism
  • Cell Line, Tumor
  • DNA, Viral / analysis
  • Follow-Up Studies
  • Gene Silencing
  • Hepatitis B virus
  • Hepatitis B, Chronic / immunology*
  • Humans
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / virology
  • Liver Neoplasms / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism*
  • Prospective Studies
  • STAT3 Transcription Factor / metabolism*
  • T-Lymphocytes, Cytotoxic / immunology
  • Tissue Array Analysis
  • Transcription Factors / metabolism*
  • Transcription, Genetic


  • 3' Untranslated Regions
  • Antiviral Agents
  • B7-H1 Antigen
  • CD274 protein, human
  • DNA, Viral
  • MIRN200 microRNA, human
  • MicroRNAs
  • SALL4 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Transcription Factors