水通道蛋白 9 表达对肾透明细胞癌预后的影响。
Prognostic implications of Aquaporin 9 expression in clear cell renal cell carcinoma.
机构信息
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
出版信息
J Transl Med. 2019 Nov 8;17(1):363. doi: 10.1186/s12967-019-2113-y.
BACKGROUND
Growing evidence has demonstrated immune reactivity as a confirmed important carcinogenesis and therapy efficacy for clear cell renal cell carcinoma (ccRCC). Aquaporin 9 (AQP9) is involved in many immune-related signals; however, its role in ccRCC remains to be elucidated. This study investigated AQP9 expression in tumor tissues and defined the prognostic value in ccRCC patients.
METHODS
A total of 913 ccRCC patients with available RNA-sequence data from the Cancer Genome Atlas (TCGA) database and Fudan University Shanghai Cancer Center (FUSCC) were consecutively recruited in analyses. Differential transcriptional and proteome expression profiles were obtained and validated using multiple datasets. A partial likelihood test from Cox regression analysis was developed to address the influence of independent factors on progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method and log-rank test were performed to assess survival. Receiver operating characteristic (ROC) curves were used to describe binary classifier value of AQP9 using area under the curve (AUC) score. Functional enrichment analyses and immune infiltration analysis were used to describe significantly involved hallmark pathways of hub genes.
RESULTS
Significantly elevated transcriptional and proteomic AQP9 expressions were found in ccRCC samples. Increased AQP9 mRNA expression was significantly associated with advanced clinicopathological parameters and correlated with shorter PFS and OS in TCGA and FUSCC cohorts (p < 0.001). ROC curves suggested the significant diagnostic and prognostic ability of AQP9 (PFS, AUC = 0.823; OS, AUC = 0.828). Functional annotations indicated that AQP9 is involved in the most significant hallmarks including complement, coagulation, IL6/JAK-STAT3, inflammatory response and TNF-alpha signaling pathways.
CONCLUSION
Our study revealed that elevated AQP9 expression was significantly correlated with aggressive progression, poor survival and immune infiltrations in ccRCC patients, and we validated its prognostic value in a real-world cohort. These data suggest that AQP9 may act as an oncogene and a promising prognostic marker in ccRCC.
背景
越来越多的证据表明，免疫反应是透明细胞肾细胞癌（ccRCC）明确的重要致癌作用和治疗效果。水通道蛋白 9（AQP9）参与许多免疫相关信号，但它在 ccRCC 中的作用仍有待阐明。本研究检测了肿瘤组织中 AQP9 的表达，并定义了其在 ccRCC 患者中的预后价值。
方法
本研究连续纳入了来自癌症基因组图谱（TCGA）数据库和复旦大学上海癌症中心（FUSCC）的 913 例 ccRCC 患者的可用 RNA 测序数据。采用多组学数据集获得并验证差异转录组和蛋白质组表达谱。采用 Cox 回归分析的部分似然检验来确定独立因素对无进展生存期（PFS）和总生存期（OS）的影响。采用 Kaplan-Meier 方法和对数秩检验评估生存情况。采用接受者操作特征（ROC）曲线描述 AQP9 的二分类器值，并采用曲线下面积（AUC）评分。采用功能富集分析和免疫浸润分析来描述关键基因显著相关的标志性通路。
结果
在 ccRCC 样本中发现 AQP9 的转录本和蛋白质表达显著升高。AQP9mRNA 表达增加与临床病理参数进展有关，且与 TCGA 和 FUSCC 队列的 PFS 和 OS 较短相关（p<0.001）。ROC 曲线表明 AQP9 具有显著的诊断和预后能力（PFS，AUC=0.823；OS，AUC=0.828）。功能注释表明 AQP9 参与了最显著的标志性通路，包括补体、凝血、IL6/JAK-STAT3、炎症反应和 TNF-α 信号通路。
结论
本研究表明，在 ccRCC 患者中，AQP9 表达升高与侵袭性进展、不良生存和免疫浸润显著相关，并且在真实世界队列中验证了其预后价值。这些数据表明，AQP9 可能作为 ccRCC 的癌基因和有前途的预后标志物。
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