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Deficient TSC1/TSC2-complex suppression of SOX9-osteopontin-AKT signalling cascade constrains tumour growth in

Fuquan Jin1, Keguo Jiang1,2, Shuang Ji1,3

  • 1Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, People's Republic of China.

Human Molecular Genetics
|December 26, 2016
PubMed

Insights

Loss of the TSC1/TSC2 complex in Tuberous Sclerosis Complex (TSC) reduces osteopontin (OPN) via SOX9, inhibiting AKT signaling. This pathway limits malignant tumor development in TSC patients.

Area of Science:

  • Genetics
  • Oncology
  • Cell Biology

Background:

  • Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder causing benign tumors due to TSC1/TSC2 complex dysfunction.
  • Hyperactive mTOR signaling and AKT feedback regulation influence TSC-associated tumor characteristics.

Purpose of the Study:

  • Investigate the role of osteopontin (OPN) in TSC pathogenesis.
  • Elucidate the mechanism by which TSC1/TSC2 complex loss affects AKT signaling.
  • Determine the impact of the SOX9-OPN-AKT pathway on tumor development in TSC.

Main Methods:

  • Analysis of OPN levels in Tsc2-deficient cells and TSC models.
  • Investigation of SOX9-mediated OPN regulation.
  • Assessment of AKT signaling and OPN abundance in TSC cells.
  • Evaluation of cell proliferation and tumor development.

Main Results:

  • Osteopontin (OPN) expression is significantly reduced in the absence of the TSC1/TSC2 complex.
  • SOX9 transcription factor mediates TSC1/TSC2 complex-dependent OPN upregulation independently of mTOR.
  • Loss of OPN contributes to AKT inactivation in TSC cells.
  • OPN abundance correlates with cell proliferation and tumor development potency.

Conclusions:

  • Loss of TSC1/TSC2 complex leads to mTOR-independent AKT inhibition, partly via downregulation of the SOX9-OPN signaling cascade.
  • The SOX9-OPN-AKT pathway acts as a safeguard against malignant tumor progression in Tuberous Sclerosis Complex.

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