Open AccessRae1 drives NKG2D binding‐dependent tumor development in mice by activating mTOR and STAT3 pathways in tumor cells
Author(s) -
Zhao Peiyan,
Yang Lei,
Li Xin,
Lu Wenting,
Lu Fangjie,
Wang Shengnan,
Wang Ying,
Hua Li,
Cui Cuiyun,
Dong Boqi,
Yu Yongli,
Wang Liying
Publication year - 2020
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14434
Subject(s) - pi3k/akt/mtor pathway , nkg2d , biology , stat3 , cancer research , immune system , microbiology and biotechnology , signal transduction , cytotoxic t cell , immunology , in vitro , biochemistry
Natural killer group 2 member D (NKG2D) ligands (NKG2DLs) on tumor cells engage NKG2D and mediate killing by NKG2D + immune cells. However, tumor cells with high levels of NKG2DLs are still malignant and proliferate rapidly. We investigated the reason for NKG2DL‐expressing cell progression. Tumor cells in mice were assessed for their NKG2DL expression, ability to attract immune cells, tumorigenicity, mTOR, and signal transducer and activator of transcription 3 (STAT3) signaling activation. Antibody blockade was used to determine the effect of NKG2DL‐NKG2D interaction on signaling activation in vitro. Retinoic acid early inducible gene 1 (Rae1) was related to the expression of other NKG2DLs, the promotion of tumorigenicity, Mmp2 expression, mTOR and STAT3 phosphorylation in GL261 cells, and the recruitment of NKG2D + cells in mice. Rae1 also induced NKG2DL expression, mTOR, and STAT3 phosphorylation in GL261 cells and LLC cells, but not in B16 and Pan02 cells, which did not express NKG2DLs, when cocultured with PBMCs; the induced phosphorylation was eliminated by Rae1‐NKG2D blockade. Inhibition of mTOR and/or STAT3 decreased PBMC‐induced migration and proliferation of GL261 cells in vitro. Rae1, a NKG2DL on tumor cells, plays a driving role in the expression of other NKG2DLs and in tumor development in mice by activating mTOR and STAT3 pathways, relying on its interaction with NKG2D on immune cells.