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Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice

Suchithra Menon1, Jessica L Yecies, Hui H Zhang

  • 1Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.

Science Signaling
|March 30, 2012
PubMed

Insights

Dysregulated mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling in normal tissues can increase cancer risk. Chronic mTORC1 activation promotes hepatocellular carcinoma development by causing liver damage and stress.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Aberrant mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling is common in human cancers.
  • The role of mTORC1 dysregulation in normal tissues regarding cancer risk is largely unknown.
  • Hepatocellular carcinoma (HCC) development is linked to environmental factors influencing mTORC1 activity, such as diet.

Purpose of the Study:

  • To investigate whether dysregulation of mTORC1 signaling in normal tissues increases cancer risk.
  • To explore the role of TSC1 (tuberous sclerosis complex 1) in mTORC1 regulation and its impact on hepatocellular carcinoma development.
  • To elucidate the molecular mechanisms linking chronic mTORC1 activation to hepatocarcinogenesis.

Main Methods:

  • Generated mice with liver-specific knockout of the Tsc1 gene to induce constitutive mTORC1 signaling.
  • Analyzed pathological changes preceding hepatocellular carcinoma development in the mouse model.
  • Investigated the roles of endoplasmic reticulum stress and autophagy defects in hepatocyte damage and cancer progression.

Main Results:

  • Liver-specific Tsc1 knockout mice developed sporadic hepatocellular carcinoma with diverse histological and biochemical features.
  • Spontaneous HCC development was preceded by liver damage, inflammation, necrosis, and regeneration.
  • Chronic mTORC1 signaling resulted in unresolved endoplasmic reticulum stress and impaired autophagy, contributing to hepatocyte damage and HCC.

Conclusions:

  • Increased activation of mTORC1 signaling in normal tissues can promote hepatocellular carcinoma development.
  • Chronic mTORC1 activation contributes to carcinogenesis through endoplasmic reticulum stress and autophagy defects.
  • mTORC1 signaling represents a potential molecular link between environmental factors, such as diet, and cancer risk.

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