PD-L2 expression in colorectal cancer: Independent prognostic effect and targetability by deglycosylation
PD-L2 expression in colorectal cancer: Independent prognostic effect and targetability by deglycosylation
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DOI：
10.1080/2162402x.2017.1327494
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发表时间：
2017-01-01
期刊：
影响因子：
7.2
通讯作者：
Xu, Jie
中科院分区：
文献类型：
--
作者：
Wang, Huanbin;Yao, Han;Xu, Jie
结直肠癌（CRC）是全球癌症死亡的第二大原因，免疫检查点阻断治疗为改善结直肠癌患者的预后提供了机会。最近的研究表明，程序性死亡配体-1 （PD-L1）仅在12%的crc中表达。在这里，我们证明PD-L2在大约40%的CRC中表达，并且其表达与CRC患者的低生存率独立相关。通过对124例有10年生存数据的CRC患者进行免疫荧光检测PD-L2表达，我们发现癌细胞中PD-L2过表达与总生存期较差之间存在显著关联（46.3 vs 69.1 mo; p = 0.0004）。在多变量COX回归分析中，相关性仍然显著（风险比= 2.778,95%可信区间[CI] D 1.668-4.627; p < 0.0001）。在验证CRC数据集中，单因素分析（27.1 vs. 88.9 mo; p = 0.0002）和多因素模型（风险比D 7.09, 95% CI 1.78-28.16; p = 0.005）支持PD-L2过表达与不良生存率之间的显著关联。Western Blot结果显示，干扰素-g （IFNg）在结直肠癌细胞中强烈诱导PD-L2表达，两种基因的mRNA水平在结直肠癌组织样本中显著相关。tunicamycin抑制糖基化导致PD-L2蛋白分子量的改变和表达的显著降低。综上所述，PD-L2在结直肠癌细胞中过表达，在IFNg和糖基化的调控下，与结直肠癌患者的低生存率相关。这些发现强调了PD-L2作为CRC的一个有希望的治疗靶点，并提出了控制CRC细胞中PD-L2表达的潜在途径。
Colorectal cancer (CRC) is the second leading cause of cancer death worldwide, and immune checkpoint blockade therapy provides an opportunity for improving the outcome of CRC patients. Recent studies suggest that programmed death ligand-1 (PD-L1) is only expressed in 12% of CRCs. Here, we demonstrate that PD-L2 is expressed in approximately 40% CRCs, and its expression independently associates with poor survival of CRC patients. By detection of PD-L2 expression by immunofluorescence in 124 CRC cases with 10-y survival data, we found significant association between PD-L2 overexpression in cancer cells and worse overall survival (46.3 vs 69.1 mo; p = 0.0004). The association remained significant in multivariate COX regression analysis (hazard ratio = 2.778, 95% confidence interval [CI] D 1.668-4.627; p < 0.0001). In the validation CRC data set, significant association between PD-L2 overexpression and poor survival was supported by the univariate analysis (27.1 vs. 88.9 mo; p = 0.0002) and multivariate model (hazard ratio D 7.09, 95% CI 1.78-28.16; p = 0.005). Western Blot revealed strong induction of PD-L2 expression by interferon-g (IFNg) in CRC cells, and the mRNA levels of both genes were significantly correlated in CRC tissue samples. Suppression of glycosylation with tunicamycin caused a shift in molecular weight and significant decrease in the expression of PD-L2 protein. In conclusion, PD-L2 overexpression in CRC cells, under the regulation by IFNg and glycosylation, associates with poor survival of patients with colorectal cancer. These findings highlight PD-L2 as a promising therapeutic target in CRC and suggest potential routes to control PD-L2 expression in CRC cells.