The Tumor Suppressor TGFBR3 Blocks Lymph Node Metastasis in Head and Neck Cancer

The TGF-beta type III receptor (TGFBR3) is an essential constituent of the TGF-beta signaling. In this study, we observed a down-regulation ofTGFBR3in oral cancer, a subtype of head and neck cancer (HNC), and patients with lowTGFBR3had poor clinical outcomes. Ectopic expression ofTGFBR3decreased migration and invasion of oral cancer cells and lymph node metastasis of tumors, whereas depletion ofTGFBR3had the opposite effect. In SMAD4-positive OC-2 oral cancer cells, TGFBR3-mediated suppression requires both of its cytoplasmic interacting partners ARRB2 and GIPC1. We demonstrated that TGFBR3 induces the abundance of secreted angiogenin (ANG), a known pro-angiogenic factor, and ANG is essential and sufficient to mediate TGFBR3-dependent inhibition of migration and invasion of oral cancer cells. Notably, inSMAD4-deficient CAL-27 oral cancer cells, only GIPC1 is essential forTGFBR3-induced suppressive activity. Accordingly, HNC patients with low expressions of bothTGFBR3andGIPC1had the poorest overall survival. In summary, we conclude that TGFBR3 is as a tumor suppressor via SMAD4-dependent and -independent manner in both tumor and stromal cells during oral carcinogenesis. Our study should facilitate the possibility of using TGFBR3-mediated tumor suppression for HNC treatment.