Abstract
TNF receptor superfamily member 11a (TNFRSF11a, RANK) and its ligand TNF superfamily member 11 (TNFRSF11, RANKL) are overexpressed in a number of malignancies. The clinical importance of RANKL/RANK in colorectal cancer (CRC) is, however, mainly unknown. We examined CRC patient samples and found that RANKL/RANK was elevated in CRC tissues as compared to nearby normal tissues. A higher RANKL/RANK expression was related with a worse survival rate. Furthermore, we found that RANKL is mostly produced by regulatory T cells (Tregs), which can promote CRC advancement. Overexpression of RANK or addition of RANKL significantly increased the stemness and migration of CRC cells. Furthermore, RANKL/RANK signaling stimulates C-C motif chemokine ligand 20 (CCL20) production by CRC cells, which leads to Treg recruitment, boosting tumor stemness and malignant progression. This recruitment process was accomplished by using CCL20-CCR6 interaction, demonstrating a connection between CRC cells and immune cells. These findings suggest that RANKL/RANK plays an important role in CRC progression and could be a potential target for CRC prevention and therapy.