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Updated: Jun 21, 2025

An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis

Published on: September 12, 2019

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FOXM1/DEPDC1 feedback loop promotes hepatocarcinogenesis and represents promising targets for cancer therapy

Teng Wei1, Chenquan Zeng1, Qineng Li1

  • 1Cytotherapy Laboratory, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China.

Cancer Science
|July 15, 2024
PubMed

Insights

The Forkhead box M1 (FOXM1) and DEP domain containing 1 (DEPDC1) axis drives cancer growth and poor outcomes in hepatocellular carcinoma. Targeting this axis with T-cell receptor-engineered T cells shows promise for immunotherapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunotherapy

Background:

  • Forkhead box M1 (FOXM1) is a critical regulator of mitosis and an oncogene implicated in various human cancers.
  • The precise mechanisms by which FOXM1 contributes to carcinogenesis and potential therapeutic strategies are not fully elucidated.

Purpose of the Study:

  • To identify and characterize a regulatory axis involving FOXM1 and its target gene DEP domain containing 1 (DEPDC1).
  • To investigate the biological functions and clinical significance of the FOXM1/DEPDC1 axis in hepatocellular carcinoma.
  • To explore the potential of targeting this axis with immunotherapy.

Main Methods:

  • Investigated the transcriptional regulation of DEPDC1 by FOXM1.
  • Assessed the interaction between FOXM1 and DEPDC1, including effects on nuclear translocation and transcriptional activity.
  • Utilized gene silencing techniques (FOXM1 knockdown, DEPDC1 silencing) in cell culture and a murine hepatocellular carcinoma model.
  • Analyzed clinical data from human hepatocellular carcinoma samples for correlations between FOXM1/DEPDC1 expression and patient outcomes.
  • Employed bioinformatic analysis to identify T-cell epitopes and developed T cell receptor (TCR)-engineered T cells for targeting FOXM1 and DEPDC1.

Main Results:

  • FOXM1 directly induces DEPDC1 expression.
  • DEPDC1 enhances FOXM1's nuclear translocation and transcriptional activity, forming a positive feedback loop.
  • The FOXM1/DEPDC1 axis is essential for cancer cell proliferation and tumor growth, with DEPDC1 rescuing growth inhibition from FOXM1 knockdown.
  • Silencing DEPDC1 significantly reduces tumor growth in a murine model of hepatocellular carcinoma.
  • High expression of the FOXM1/DEPDC1 axis correlates with poor clinical outcomes in human hepatocellular carcinoma patients.
  • TCR-engineered T cells targeting FOXM1 epitopes (FOXM1262-270) and DEPDC1 epitopes (DEPDC1294-302) effectively eradicated tumor cells in vitro.

Conclusions:

  • The FOXM1/DEPDC1 regulatory axis plays a crucial role in hepatocarcinogenesis.
  • This axis represents a significant therapeutic target for hepatocellular carcinoma.
  • TCR-engineered T cell therapy targeting FOXM1 or DEPDC1 is a viable strategy for treating hepatocellular carcinoma.
Keywords:
DEPDC1FOXM1TCR‐engineered T cellshepatocellular carcinomamitosis regulator

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