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Suppressive Effect of Autocrine FGF21 on Autophagy-Deficient Hepatic Tumorigenesis

Jinyoung Kim1, Soyeon Lee1,2, Myung-Shik Lee1,3,4

  • 1Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea.

Frontiers in Oncology
|March 24, 2022
PubMed

Insights

Autophagy deficiency in liver cells promotes hepatoma. Fibroblast growth factor 21 (FGF21) produced by these cells accelerates tumor growth by increasing cell proliferation and DNA damage, worsening prognosis.

Area of Science:

  • Cell Biology
  • Oncology
  • Metabolism

Background:

  • Autophagy is crucial for cellular health; its deficiency, specifically in hepatocytes (liver cells), is linked to hepatoma development.
  • Fibroblast growth factor 21 (FGF21), a 'mitokine,' is upregulated when autophagy-related 7 (Atg7) is disrupted in liver tissues, potentially influencing systemic metabolism.
  • FGF21 and related FGFs are known to impact tumor progression, suggesting a role in autophagy-deficient hepatoma.

Purpose of the Study:

  • To investigate the autocrine effect of FGF21 produced by Atg7-knockout (KO) hepatocytes on the behavior of autophagy-deficient hepatoma.
  • To determine how FGF21 influences hepatoma proliferation, size, and number in a genetic model of autophagy deficiency.

Main Methods:

  • Generation of Atg7 ΔHep Fgf21 -/- mice by crossing Atg7 ΔHep mice with systemic Fgf21-KO mice.
  • Analysis of hepatoma number, size, and hepatocyte proliferation in Atg7 ΔHep mice with and without Fgf21 KO.
  • Assessment of YAP1 degradation, YAP1/TAZ downstream gene expression, reactive oxygen species (ROS) accumulation, and ROS-mediated DNA damage in the liver.

Main Results:

  • Hepatoma number and size were significantly increased in Atg7 ΔHep mice lacking Fgf21 (Atg7 ΔHep Fgf21 -/-) compared to those with intact Fgf21 (Atg7 ΔHep Fgf21 +/+).
  • Hepatocyte proliferation was significantly elevated in Atg7-KO hepatocytes when Fgf21 was absent.
  • YAP1 degradation decreased, YAP1/TAZ gene expression increased, and ROS-mediated DNA damage was aggravated in Atg7 ΔHep Fgf21 -/- mice, correlating with increased hepatoma size and number.

Conclusions:

  • FGF21 produced by autophagy-deficient hepatocytes exerts autocrine or paracrine effects that influence the proliferation and number of autophagy-deficient hepatoma.
  • Factors released from autophagy-deficient tumors, such as FGF21, can modulate tumor behavior and prognosis, extending beyond their impact on host metabolism.
  • Targeting FGF21 signaling may offer a therapeutic strategy for managing hepatoma associated with autophagy deficiency.
Keywords:
FGF21 (fibroblast growth factor 21)ROS (reactive oxygen species)YAP1/TAZ pathwayautophagyhepatic tumor

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