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Rae1 drives NKG2D binding-dependent tumor development in mice by activating mTOR and STAT3 pathways in tumor cells

Peiyan Zhao1, Lei Yang1, Xin Li1

  • 1Department of Molecular Biology, College of Basic Medical Sciences and Institute of Pediatrics, The First Hospital of Jilin University, Jilin University, Changchun, China.

Cancer Science
|April 26, 2020
PubMed

Insights

Tumor cells expressing Natural Killer Group 2 Member D ligands (NKG2DLs) still grow. Retinoic acid early inducible gene 1 (Rae1) drives tumor progression by activating mTOR and STAT3 pathways via NKG2D interaction.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • Natural Killer Group 2 Member D (NKG2D) ligands (NKG2DLs) on tumor cells engage NKG2D+ immune cells for tumor cell killing.
  • Despite NKG2DL expression, some tumor cells exhibit high malignancy and rapid proliferation, suggesting underlying escape mechanisms.

Purpose of the Study:

  • To investigate the mechanisms behind the progression of NKG2DL-expressing tumor cells.
  • To elucidate the role of Retinoic acid early inducible gene 1 (Rae1) in tumor development and immune cell interaction.

Main Methods:

  • Assessment of NKG2DL expression, immune cell recruitment, tumorigenicity, mTOR, and STAT3 signaling in mouse tumor models.
  • In vitro antibody blockade to study NKG2DL-NKG2D interaction effects on signaling.
  • Co-culture experiments with peripheral blood mononuclear cells (PBMCs) and tumor cell lines.

Main Results:

  • Rae1 expression correlated with other NKG2DLs, enhanced tumorigenicity, Mmp2 expression, and mTOR/STAT3 phosphorylation in GL261 cells.
  • Rae1 induced NKG2DL expression and mTOR/STAT3 phosphorylation in GL261 and LLC cells, an effect blocked by Rae1-NKG2D antibody.
  • Inhibition of mTOR and/or STAT3 reduced PBMC-induced migration and proliferation of GL261 cells.

Conclusions:

  • Rae1 acts as a key NKG2DL driving tumor development in mice.
  • Rae1 activates mTOR and STAT3 pathways through interaction with NKG2D on immune cells, promoting tumor progression and immune cell recruitment.
Keywords:
mTORnatural killer group 2 member D ligandsretinoic acid early inducible gene 1signal transducer and activator of transcription 3tumor development

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