1] Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Department of Oncology and Department of Pathology, The University of Melbourne, Parkville, Victoria 3000, Australia.
1] Sir Peter MacCallum Department of Oncology and Department of Pathology, The University of Melbourne, Parkville, Victoria 3000, Australia [2] Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
Br J Cancer. 2014 Mar 18;110(6):1606-13. doi: 10.1038/bjc.2014.31. Epub 2014 Feb 18.
RAD21 is a component of the cohesion complex and is integral to chromosome segregation and error-free DNA repair. RAD21 is functionally important in tumour progression but its role in colorectal carcinoma (CRC) is unclear. We therefore assessed its clinicopathological and prognostic significance in CRC, as well as its effect on chemosensitivity.
A retrospective observation study examined RAD21 expression in 652 CRCs using a tissue microarray approach. Correlation with clinicopathological factors including gender, tumour grade, mucinous subtype, TNM stage, disease-specific survival (DSS), BRAF and KRAS mutation status, tumour p53 immunostaining, tumour microsatellite instability and tumour CpG island methylator phenotype was performed. Colorectal cancer cell clones with stable RAD21 knockdown were generated and tested for cellular sensitivity to conventional chemotherapeutic drugs.
RAD21 expression was significantly correlated with male gender (56.7% vs 43.3%, P=0.02), well-differentiated histology (14.4% vs 4.0%, P=0.0001), higher T-stage (36.1% vs 27.0%, P=0.01), presence of metastasis (18.8% vs 12.6%, P=0.03), and shorter DSS (hazard ratio (HR) 1.4, 95% CI 1.1 to 1.9, P=0.01) in both univariate and multivariate analysis. RAD21 expression was associated with shorter DSS in patients with KRAS mutant tumours (HR:2.6, 95% CI:1.4-4.3, P=0.001) and in patients receiving adjuvant chemoradiotherapy (HR:1.9, 95% CI:1.2-3.0, P=0.008). Colorectal cancer cells with RAD21 knockdown exhibited enhanced sensitivity to 5-fluorouracil, either alone or in combination with oxaliplatin.
RAD21 expression in CRC is associated with aggressive disease especially in KRAS mutant tumours and resistance to chemoradiotherapy. RAD21 may be an important novel therapeutic target.
RAD21 是黏合复合物的一个组成部分，对于染色体分离和无差错 DNA 修复至关重要。RAD21 在肿瘤进展中具有重要的功能，但在结直肠癌（CRC）中的作用尚不清楚。因此，我们评估了 RAD21 在 CRC 中的临床病理和预后意义，以及其对化疗敏感性的影响。
采用组织微阵列方法对 652 例 CRC 进行了 RAD21 表达的回顾性观察研究。分析了 RAD21 表达与性别、肿瘤分级、黏液型亚型、TNM 分期、疾病特异性生存（DSS）、BRAF 和 KRAS 突变状态、肿瘤 p53 免疫组化、肿瘤微卫星不稳定性和肿瘤 CpG 岛甲基化表型等临床病理因素的相关性。生成了稳定 RAD21 敲低的结直肠癌细胞克隆，并检测了它们对常规化疗药物的细胞敏感性。
RAD21 表达与男性（56.7%比 43.3%，P=0.02）、分化良好的组织学（14.4%比 4.0%，P=0.0001）、较高的 T 分期（36.1%比 27.0%，P=0.01）、转移存在（18.8%比 12.6%，P=0.03）以及较短的 DSS（风险比（HR）1.4，95%CI 1.1 至 1.9，P=0.01）有关，这在单变量和多变量分析中均成立。RAD21 表达与 KRAS 突变肿瘤患者（HR：2.6，95%CI：1.4-4.3，P=0.001）和接受辅助放化疗的患者（HR：1.9，95%CI：1.2-3.0，P=0.008）的较短 DSS 相关。RAD21 敲低的结直肠癌细胞对 5-氟尿嘧啶（5-FU）单独或与奥沙利铂联合使用的敏感性增强。
CRC 中 RAD21 的表达与侵袭性疾病相关，特别是在 KRAS 突变肿瘤中，并且对放化疗有耐药性。RAD21 可能是一个重要的新的治疗靶点。
