Department of Gastroenterology, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, China.
Jiangsu Key Laboratory of Clinical Immunology, Soochow University, 708 Renmin Road, Suzhou, China.
Cell Death Dis. 2020 Oct 3;11(10):824. doi: 10.1038/s41419-020-03041-4.
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.
作为结直肠癌（CRC）局部控制的重要方式，放疗或新辅助放疗在临床上得到广泛应用，但放射抵抗已成为 CRC 放疗的主要障碍。我们在此报道，B7-H3，一种重要的共刺激分子，与 CRC 的放射抵抗有关。照射后 CRC 细胞中 B7-H3 的表达明显增加。B7-H3 的增强表达促进了照射后 CRC 细胞的集落形成和细胞活性，而 B7-H3 的敲低则抑制了这一过程。B7-H3 过表达减少了 S 期阻滞并保护了细胞凋亡，而 B7-H3 敲低则产生相反的效果。此外，特异性 B7-H3 抗体 3E8 阻断 B7-H3，可显著增强 CRC 细胞对体内照射的敏感性。机制分析表明，B7-H3 通过 RNA 测序调节 KIF15，这独立于 NF-κB 通路。并且，siRNA 介导的 KIF15 沉默或抑制剂 SB743921 阻断 KIF15 可消除 B7-H3 对体外和体内放射抵抗的影响。与 B7-H3 相似，我们发现 KIF15 的蛋白表达水平在癌症组织中异常上调，与相邻正常组织相比呈正相关，并且与 TNM 分期相关。最后，B7-H3/KIF15 通过激活 ERK1/2 信号通路增强 CRC 细胞对辐射的抵抗，ERK1/2 信号通路是癌症放射抵抗的关键途径。我们的研究结果揭示了 CRC 细胞通过 B7-H3/KIF15/ERK 轴获得放射抵抗的另一种机制。
