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Thyroid hormone suppresses hepatocarcinogenesis via DAPK2 and SQSTM1-dependent selective autophagy

Hsiang-Cheng Chi1, Shen-Liang Chen2, Chung-Ying Tsai1

  • 1a Department of Biochemistry , College of Medicine, Chang-Gung University , Taoyuan , Taiwan.

Autophagy
|September 23, 2016
PubMed

Insights

Thyroid hormone (TH) protects against liver cancer (HCC) by activating autophagy. This process involves DAPK2 and SQSTM1, clearing damaged proteins and preventing cancer development in a mouse model.

Area of Science:

  • Hepatocellular carcinoma (HCC) research
  • Thyroid hormone (TH) signaling
  • Autophagy and cellular regulation

Background:

  • Disrupted thyroid hormone (TH) signaling is linked to hepatocellular carcinoma (HCC).
  • Mechanisms underlying TH's role in HCC development are not fully understood.
  • TH's potential protective effects against liver cancer warrant further investigation.

Purpose of the Study:

  • To elucidate the mechanisms by which thyroid hormone (TH) influences hepatocellular carcinoma (HCC) progression.
  • To investigate the role of autophagy in TH-mediated protection against liver cancer.
  • To identify key molecular players in the TH-autophagy pathway relevant to HCC.

Main Methods:

  • Utilized a diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) murine model.
  • Administered TH and autophagy inhibitors (chloroquine) or used gene knockdown (ATG7, DAPK2) via AAV vectors.
  • Analyzed autophagic activity, protein aggregation, DNA damage, and expression of TH receptors (THRs) and DAPK2.

Main Results:

  • Disruption of TH production accelerated DEN-induced HCC; TH administration suppressed it.
  • TH-mediated protection against hepatic damage and HCC was dependent on autophagy.
  • TH activated DAPK2, promoting SQSTM1/p62 phosphorylation and selective autophagy, which reduced DEN-induced hepatotoxicity and DNA damage.

Conclusions:

  • Thyroid hormone (TH) protects hepatocytes from injury and carcinogenesis by inducing selective autophagy.
  • The DAPK2-SQSTM1 pathway is crucial for TH-mediated autophagic clearance and hepatoprotection.
  • TH signaling, through DAPK2-mediated autophagy, represents a potential therapeutic target for hepatocellular carcinoma (HCC).
Keywords:
DAPK2HCCSQSTM1/p62THRselective autophagy

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