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

Yanchao Ma,Weichang Chen,Ruoqin Wang,Shenghua Zhan,Lei Cao,Huimin Lu,Guangbo Zhang,Xueguang Zhang,Tongguo Shi,Yunyun Xu

doi:10.1038/s41419-020-03041-4

Yanchao Ma, Weichang Chen + Show 8 more

Open Access

https://doi.org/10.1038/s41419-020-03041-4

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Abstract

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.

Highlights

Colorectal cancer (CRC) is the third most commonly occurring malignancy and accounts for more than 9% of all cancer-related deaths worldwide[1]
B7-H3 enhances the radioresistance of CRC cells in vitro As shown in Supplementary Fig. S1a, B7-H3 was frequently upregulated in the CRC cell lines (RKO, HCT116, HCT8, HT29, SW480 and SW620) compared to the human colon healthy cell line (NCM460), suggesting B7H3 overexpression has a crucial role in CRC progression
To better understand the link between B7-H3 and CRC radioresistance, we first investigated the expression of B7H3 in CRC cells after ionizing radiation (IR)

Summary

Introduction

Colorectal cancer (CRC) is the third most commonly occurring malignancy and accounts for more than 9% of all cancer-related deaths worldwide[1]. Neoadjuvant radiotherapy/chemoradiotherapy (neoRT/CRT) following surgery has been approved by NCCN and is required for comprehensive therapy for locally advanced stage II and III CRC2. Preoperative chemoradiotherapy combined with surgery could improve the locoregional control of CRC. The treatment effect of both neoRT/CRT and preoperative chemoradiotherapy is still unsatisfactory because of chemoresistance and radioresistance[3]. Approximately 50% of CRC patients experience recurrence and metastasis after radiotherapy[4]. There is an urgent need to understand the mechanisms of radioresistance and identify biomarkers that predict radioresistance in CRC patients

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