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TIS21 negatively regulates hepatocarcinogenesis by disruption of cyclin B1-Forkhead box M1 regulation loop

Tae Jun Park1, Ji Yeon Kim, S Paul Oh

  • 1Department of Biochemistry and Molecular Biology, Ajou University, School of Medicine, Suwon, Republic of Korea.

Hepatology (Baltimore, Md.)
|April 9, 2008
PubMed
Abstract

Insights

Tissue-specific extinguisher 21 (TIS21) inhibits hepatocellular carcinoma (HCC) growth by disrupting the FoxM1-cyclin B1 pathway. This finding reveals TIS21

Area of Science:

  • Hepatology
  • Molecular Biology
  • Oncology

Background:

  • Hepatocellular carcinoma (HCC) is a major global health concern.
  • Forkhead box M1 (FoxM1) is a key regulator of cell proliferation and liver regeneration.
  • The role of TIS21 (also known as BTG2/PC3) in HCC development requires further elucidation.

Purpose of the Study:

  • To investigate the functional and biochemical interaction between TIS21 and FoxM1.
  • To explore the role of TIS21 in regulating HCC growth and proliferation.
  • To elucidate the molecular mechanisms by which TIS21 influences hepatocarcinogenesis.

Main Methods:

  • Murine model of diethylnitrosamine (DEN)-induced HCC.
  • TIS21 knockout (TIS21(-/-)) and wild-type (TIS21(+/+)) mice.
  • In vitro kinase assays and FoxM1 mutant analyses.
  • Analysis of human and murine HCC tissues.
  • Cell proliferation and tumorigenicity assays in Huh7 cells.

Main Results:

  • HCC growth was significantly higher in TIS21(-/-) mice at 9 months post-DEN injection.
  • TIS21 expression was downregulated in both human and murine HCCs compared to surrounding tissues.
  • Forced TIS21 expression reduced proliferation and tumorigenicity of HCC cells.
  • TIS21 inhibited FoxM1 phosphorylation by reducing cyclin B1-cdk1 activity.

Conclusions:

  • TIS21 negatively regulates hepatocarcinogenesis.
  • TIS21 disrupts the FoxM1-cyclin B1 regulatory loop, inhibiting proliferation of transformed liver cells.
  • TIS21 represents a potential therapeutic target for HCC.

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