Department of Urology, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou 310009, China.
Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou 310024, China.
Int J Mol Sci. 2023 Apr 19;24(8):7505. doi: 10.3390/ijms24087505.
The tumor microenvironment (TME) plays an important part in the initiation and development of clear cell renal cell carcinoma (ccRCC). However, an understanding of the immune infiltration in TME is still unknown. Our study aims to explore the correlation between the TME and the clinical features, as well as the prognosis of ccRCC. In the present study, ESTIMATE and CIBERSORT computational methods were applied to calculate the proportion of tumor-infiltrating immune cells (TICs) and the amount of immune and stromal fractions in the ccRCC form The Cancer Genome Atlas (TCGA) database. Then, we sought to find out those immune cell types and genes which may play a significant role and validated them in the GEO database. Furthermore, an immunohistochemical analysis of our external validation dataset was used to detect SAA1 and PDL1 expression in the ccRCC cancer tissues and corresponding normal tissues. Statistical analysis was performed to study the relationship between SAA1 and clinical characteristics, as well as PDL1 expression. Furthermore, a ccRCC cell model with SAA1 knockdown was constructed, which was used for cell proliferation and the migration test. The intersection analysis of the univariate COX and PPI analysis were performed to imply Serum Amyloid A1 (SAA1) as a predictive factor. The expression of SAA1 was significantly negatively correlated to OS and positively correlated to the clinical TMN stage system. The genes in the high-expression SAA1 group were basically enriched in immune-related activities. The proportion of mast cells resting was negatively correlated with SAA1 expression, indicating that SAA1 may be involved in the maintenance of the immune status for the TME. Moreover, the PDL1 expression was positively related to the SAA1 expression and negatively correlated with the patients' prognosis. Further experiments revealed that the knockdown of SAA1 inhibited ccRCC development through suppressing cell proliferation and migration. SAA1 may be a novel marker for the prognosis prediction of ccRCC patients and may play a vital role in the TME by mast cell resting and PDL1 expression. SAA1 has the potential to become a therapeutic target and indicator for immune target therapy in ccRCC treatment.
肿瘤微环境（TME）在透明细胞肾细胞癌（ccRCC）的发生和发展中起着重要作用。然而，人们对 TME 中的免疫浸润仍知之甚少。本研究旨在探讨 TME 与 ccRCC 的临床特征和预后之间的相关性。在本研究中，应用 ESTIMATE 和 CIBERSORT 计算方法从癌症基因组图谱（TCGA）数据库中计算 ccRCC 中肿瘤浸润免疫细胞（TIC）的比例和免疫及基质分数的量。然后，我们试图在 GEO 数据库中找到可能发挥重要作用的免疫细胞类型和基因，并对其进行验证。此外，我们还对外部验证数据集进行了免疫组织化学分析，以检测 ccRCC 癌组织和相应正常组织中 SAA1 和 PDL1 的表达。统计学分析用于研究 SAA1 与临床特征的关系以及 PDL1 的表达。此外，构建了 SAA1 敲低的 ccRCC 细胞模型，用于细胞增殖和迁移试验。通过单变量 COX 和 PPI 分析的交集分析表明，血清淀粉样蛋白 A1（SAA1）是一个预测因子。SAA1 的表达与 OS 显著负相关，与临床 TMN 分期系统呈正相关。高表达 SAA1 组的基因基本富集在免疫相关活性中。静止肥大细胞的比例与 SAA1 表达呈负相关，表明 SAA1 可能参与维持 TME 的免疫状态。此外，PDL1 的表达与 SAA1 的表达呈正相关，与患者的预后呈负相关。进一步的实验表明，SAA1 的敲低通过抑制 ccRCC 的发展来抑制 ccRCC 的发展。SAA1 可能是 ccRCC 患者预后预测的新标志物，通过静止肥大细胞和 PDL1 表达在 TME 中发挥重要作用。SAA1 有可能成为 ccRCC 治疗中免疫靶向治疗的治疗靶点和标志物。
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