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

Natural killer group 2 member D (NKG2D) ligands (NKG2DLs) on tumor cells engage NKG2D and mediate the killing by NKG2D(+) immune cells. However, tumor cells with high 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. The antibody blockade was used to determine the effect of NKG2DL-NKG2D interaction on the 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, and the induced phosphorylation was eliminated by Rae1-NKG2D blockade. The inhibition of mTOR and/or STAT3 decreased the PBMC-induced migration and proliferation of GL261 cells in vitro. Rae1, a NKG2DL on the tumor cells, plays a driving role on other NKG2DL expression and tumor development in mice by activating mTOR and STAT3 pathways relying on its interaction with NKG2D on immune cells.