Research

Molecular and immune mechanisms of viral hepatitis and hepatocellular carcinoma

The Project Leader's Profile

Tetsuo Takehara

Professor, Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine
Director, Osaka University Hospital

1972, MD, Osaka University Medical School; 1979, Research Fellow, Department of Biochemistry, The University of Texas; 1981, PhD, Assistant Professor, The First Department of Medicine, Osaka University Medical School; 1987, Associate Professor, The First Department of Medicine, Osaka University Medical School; 1998, Professor, Osaka University Graduate School of Medicine; 2007, Director, Osaka University Hospital
Specialty, Gastroenterology and Hepatology
Selected Books, "Standard Textbook of Gastroenterology" "Chronic hepatitis C"
Award, The JSH Award (ODA Award)

Project Leader
  • Norio Hayshi, MD, PhD, Professor, Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine
    Director, Osaka University Hospital
Research Members
  • Tetsuo Takehara, MD, PhD, Associate Professor, Department of Gastroenterology and Hepatology
  • Tatsuya Kanto, MD, PhD, Endowed Associate Professor, Department of Dendritic Cell Biology and Clinical Application
  • Tomohide Tatsumi, MD, PhD, Assistant Professor, Department of Gastroenterology and Hepatology
  • Takuya Miyagi, MD, PhD, Specially Appointed Assistant Professor, Department of Gastroenterology and Hepatology
Research Collaborators
  • Naoki Hiramatsu, MD, PhD, Associate Professor, Department of Gastroenterology and Hepatology
  • Hisashi Ishida, MD, PhD, Endowed Assistant Professor, Department of Dendritic Cell Biology and Clinical Application

Summary

More than 500 million people are persistently infected with hepatitis B or C virus in the world. Persistent infection of those viruses causes chronic liver injury, predisposing for hepatocellular carcinoma (HCC). To explore the underlying mechanisms of persistent infection and liver carcinogenesis, we are studying 1) virus-host relationship of hepatitis virus infection, 2) innate immune response for hepatitis viruses and liver tumors and 3) molecular mechanisms of liver cell death and fibrosis. Although hepatitis viruses do not infect small animals and inefficiently replicates in cultured cells, in vivo or in vitro transfer of viral genomes could provide useful tools for studying replication of the viruses. HCV infection affects the JAK/STAT signaling of host cells while the MAP kinase pathway inhibits HCV replication, suggesting novel targets for anti-HCV therapy. In patients with chronic hepatitis C, dendritic cells are decreased in number and functionally impaired. The ability of natural killer cells to respond to liver tumor cells is impaired due to increased expression of the NKG2A inhibitory receptor and decreased expression of the NKG2D activating receptors. HCC expresses and sheds MHC class I-related chain A (MICA), a ligand of NKG2D, which binds and downregulates the NKG2D receptor. The levels of soluble MICA in circulation increase as disease progresses, negatively correlating with decrease in NK cell expression of NKG2D. MICA shedding is a promising therapeutic target to improve immune response to HCC. Conditional knockout of targeted gene revealed that Bcl-xL and Mcl-1 play critical and non-redundant roles in ensuring integrity of hepatocytes in developing and adult liver. They are highly expressed and confer apoptosis resistance in HCC through micrRNA-mediated post-transcriptional regulation and a unique post-translational modification. The Bcl-2 network regulates liver development, homeostasis and carcinogenesis.

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Some of Recent Papers

  1. Sakamori R, Takehara T, Ohnishi C, Tatsumi T, Ohkawa K, Takeda K, Akira S, Hayashi N. Signal transducer and activator of transcription 3 signaling within hepatocytes attenuates systemic inflammatory response and lethality in septic mice. Hepatology 46: 1564-1573, 2007.
  2. Tatsumi T, Takehara T, Yamaguchi S, Sasakawa A, Sakamori R, Ohkawa K, Kohga K, Uemura A, Hayashi N. Intrahepatic delivery of α-galactosylceramide-pulsed dendritic cells suppresses liver tumor. Hepatology 45: 22-30, 2007.
  3. Jinushi M, Takehara T, Tatsumi T, Kanto T, Miyagi T, Suzuki T, Kanazawa Y, Hiramatsu N, Hayashi N. Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. J Immunol 173: 6072-6081, 2004.
  4. Miyagi T, Takehara T, Tatsumi T, Suzuki T, Jinushi M, Kanazawa Y, Hiramatsu N, Kanto T, Tsuji S, Hori M, Hayashi N. Concanavarin A injection activates intrahepatic innate immune cells to provoke an anti-tumor effect in murine liver. Hepatology 40: 1190-1196, 2004.
  5. Takehara T, Tatsumi T, Suzuki T, Rucker III EB, Hennighausen L, Jinushi M, Miyagi T, Kanazawa Y, Hayashi N. Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses. Gastroenterology 127: 1189-1197, 2004.