State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China.
Clin Cancer Res. 2019 Jul 15;25(14):4567-4579. doi: 10.1158/1078-0432.CCR-18-3735. Epub 2019 Apr 12.
Neoadjuvant chemoradiotherapy (neoCRT) is a standard treatment for locally advanced rectal cancer (LARC); however, resistance to chemoradiotherapy is one of the main obstacles to improving treatment outcomes. The goal of this study was to identify factors involved in the radioresistance of colorectal cancer and to clarify the underlying mechanisms.
A genome-wide RNAi screen was used to search for candidate radioresistance genes. After knockdown or overexpression, colorectal cancer cells exposed to X-rays both and in a mouse model were assayed for DNA damage, cytotoxicity, and apoptosis. Moreover, the regulatory effects and mechanisms of RFC4 in DNA repair were investigated . Finally, the relationships between expression and clinical parameters and outcomes were investigated in 145 patients with LARC receiving neoCRT.
, , , , , and were identified as potential candidate radioresistance genes. RFC4 protected colorectal cancer cells from X-ray-induced DNA damage and apoptosis and . Mechanistically, RFC4 promoted nonhomologous end joining (NHEJ)-mediated DNA repair by interacting with Ku70/Ku80 but did not affect homologous recombination-mediated repair. Higher expression in cancer tissue was associated with weaker tumor regression and poorer prognosis in patients with LARC treated with neoCRT, which likely resulted from the effect of RFC4 on radioresistance, not chemoresistance.
RFC4 was identified as a radioresistance factor that promotes NHEJ-mediated DNA repair in colorectal cancer cells. In addition, the expression level of predicted radiotherapy responsiveness and the outcome of neoadjuvant radiotherapy in patients with LARC.
新辅助放化疗（neoCRT）是局部晚期直肠癌（LARC）的标准治疗方法；然而，对放化疗的耐药性是改善治疗效果的主要障碍之一。本研究的目的是确定结直肠癌放射抵抗相关的因素，并阐明其潜在机制。
采用全基因组 RNAi 筛选寻找候选放射抵抗基因。在敲低或过表达后，用 X 射线照射和在小鼠模型中照射，检测大肠癌细胞的 DNA 损伤、细胞毒性和细胞凋亡。此外，还研究了 RFC4 在 DNA 修复中的调控作用及其机制。最后，在 145 例接受 neoCRT 的 LARC 患者中，研究了 表达与临床参数和结果的关系。
鉴定出 、 、 、 、 和 作为潜在的候选放射抵抗基因。RFC4 保护结直肠癌细胞免受 X 射线诱导的 DNA 损伤和细胞凋亡。机制上，RFC4 通过与 Ku70/Ku80 相互作用促进非同源末端连接（NHEJ）介导的 DNA 修复，但不影响同源重组介导的修复。在接受 neoCRT 治疗的 LARC 患者中，肿瘤组织中 表达较高与肿瘤退缩较弱和预后较差相关，这可能是由于 RFC4 对放射抵抗的影响，而不是对化疗耐药的影响。
RFC4 被鉴定为一种放射抵抗因子，可促进结直肠癌细胞中 NHEJ 介导的 DNA 修复。此外， 表达水平可预测 LARC 患者接受新辅助放疗的放疗反应性和结果。
