B7-H3 regulates KIF15-activated ERK1/2 pathway and contributes to radioresistance in colorectal cancer.

As an important modality for the local control of colorectal cancer (CRC), radiotherapy or neoadjuvant radiotherapy is widely applied in the clinic, but radioresistance has become a major obstacle for CRC radiotherapy. Here we reported that B7-H3, an important costimulatory molecule, is associated with radioresistance in CRC. The expression of B7-H3 was obviously increased in CRC cells after irradiation. The enhanced expression of B7-H3 promoted, while the knockdown of B7-H3 inhibited, colony formation and cell activity in CRC cells following radiation treatment. B7-H3 overexpression reduced S phase arrest and protected cell apoptosis induced by radiation, whereas B7-H3 knockdown had the opposite effects. In addition, B7-H3 blockade by 3E8, a specific B7-H3 antibody, significantly sensitized CRC cells to irradiation in vivo. Mechanistic analysis revealed that B7-H3 regulated KIF15 via RNA sequencing, which was in dependent of NF-κB pathway. And small interfering RNA (siRNA)-mediated KIF15 silencing or KIF15 blockade by the inhibitor SB743921 abolished the effect of B7-H3 on radioresistance in vitro and in vivo. Similar to B7-H3, we find that the protein expression levels of KIF15, which showed a positive correlation with B7-H3, was abnormal upregulated in cancer tissues than in adjacent normal tissues and associated with TNM stage. Finally, B7-H3/KIF15 enhanced resistance against irradiation in CRC cells via activating ERK1/2 signaling, a key pathway involved in radioresistance in cancer. Our findings reveal an alternative mechanism by which CRC cells can acquire radioresistance via the B7-H3/KIF15/ERK axis.