Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
Department of Urology, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou 215228, China.
Aging (Albany NY). 2023 Sep 8;15(17):8908-8929. doi: 10.18632/aging.205005.
The association between ccRCC and Anoikis remains to be thoroughly investigated.
Anoikis-related clusters were identified using NMF. To identify prognostic anoikis-related genes (ARGs) and establish an optimal prognostic model, univariate Cox and LASSO regression were employed. The E-MTAB-1980 cohort was utilized for external validation. Multiple algorithms were used to evaluate the immune properties of the model. GO, KEGG and GSVA analyses were employed to analyze biological pathway functions. qRT-PCR was employed to measure RNA levels of specific genes. Cell Counting Kit-8, wound healing, and Transwell chamber assays were performed to determine changes in the proliferative and metastatic abilities of A498 and 786-O cells.
Based on the expression of 21 prognostic ARGs, we constructed anoikis-related clusters with different prognostic and immune characteristics. The cluster A1 showed a worse prognosis, higher infiltration of immunosuppressive cells and enrichment of several oncogenic pathways. We also calculated the Anoikis Index (AI). Patients in high AI group had a worse prognosis, higher infiltration of immunosuppressive cells and higher expression of immunosuppressive checkpoints. TIMP1 exerted a tumor-promoting role in ccRCC and was significantly associated with immunosuppressive cells and checkpoints. The downregulation of TIMP1 negatively regulated ccRCC cell proliferation and metastasis.
ARGs played crucial roles in tumorigenesis and progression and were positively associated with a poor prognosis. AI had great accuracy in predicting the prognosis and immune characteristics of ccRCC patients. TIMP1 was significantly associated with clinicopathological variables and the immunosuppressive microenvironment, which could be exploited to design novel immunotherapies for ccRCC patients.
ccRCC 与细胞凋亡的关联仍需深入研究。
使用 NMF 鉴定与细胞凋亡相关的聚类。采用单变量 Cox 和 LASSO 回归鉴定预后相关的凋亡基因（ARGs）并建立最优预后模型。采用 E-MTAB-1980 队列进行外部验证。采用多种算法评估模型的免疫特性。GO、KEGG 和 GSVA 分析用于分析生物学途径功能。qRT-PCR 用于测量特定基因的 RNA 水平。细胞计数试剂盒-8、划痕愈合和 Transwell 室分析用于测定 A498 和 786-O 细胞增殖和转移能力的变化。
基于 21 个预后相关 ARGs 的表达，我们构建了具有不同预后和免疫特征的细胞凋亡相关聚类。A1 聚类显示预后较差，免疫抑制细胞浸润增加，多个致癌途径富集。我们还计算了凋亡指数（AI）。高 AI 组患者预后较差，免疫抑制细胞浸润增加，免疫抑制检查点表达增加。TIMP1 在 ccRCC 中发挥促肿瘤作用，与免疫抑制细胞和检查点显著相关。TIMP1 的下调负调控 ccRCC 细胞的增殖和转移。
ARGs 在肿瘤发生和进展中发挥关键作用，并与不良预后显著相关。AI 对预测 ccRCC 患者的预后和免疫特征具有很高的准确性。TIMP1 与临床病理变量和免疫抑制微环境显著相关，可用于设计针对 ccRCC 患者的新型免疫疗法。
