Meng Yuhao, Zhang Chen, Fu Tongfei, He Jiaheng, Wu Junsong, Zhan Yongli
College of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, China.
College of Clinical Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, China.
Environ Toxicol. 2025 Jun;40(6):E74-E91. doi: 10.1002/tox.24190. Epub 2024 Mar 15.
The treatment of clear-cell renal cell carcinoma (ccRCC) remains challenge. Chemokines laid impact on the proliferation and metastasis of cancer cells. The objective was to identify the chemokine-related genes and construct a prognostic model for ccRCC.
Bulk transcriptomic data (n = 531), single-cell RNA sequencing (scRNA-seq) dataset GSE159115, and other validation cohorts were acquired from the Cancer Genome Atlas Program (TCGA) and GEO databases. All clustering analysis was conducted by Seurat R package. Gene set enrichment analysis (GSEA), immune infiltration analysis, single nucleotide variations (SNV) analysis, and predictive response analysis of immunotherapy/chemotherapy were conducted. 786-O and A498 cell lines were cultured and applied into CCK-8, Western blot, and RT-qPCR kits.
Univariate Cox analysis was used to screen out chemokine-related genes related to survival. ZIC2, SMIM24, COL7A1, IGF2BP3, ITPKA, ADAMTS14, CYP3A7, and AURKB were identified and applied for the construction of the prognostic model. High-risk group had a poorer prognosis than the low-risk group in each dataset. Memory CD8+ T cells, macrophages, and memory B cells were higher in the high-risk group, while the content of basophils was higher in the low-risk group. Bortezomib_1191, Dactinomycin_1911, Docetaxel_1007, and Daporinad_1248 were more sensitive to high-risk groups than low-risk groups. Moreover, we found that IGF2BP3 significantly elevated in both 786-O and A498 cell lines resistance to sunitinib. Knockdown of IGF2BP3 markedly reduced ccRCC cell migration and viability.
Our study has yielded a novel prognostic model of chemokine-related genes based on comprehensive transcriptional atlas of ccRCC patients, shedding light on the significant impact of the tumor microenvironment on biology and immunotherapy response of ccRCC. We identified IGF2BP3 as a pivotal regulator in regulating ccRCC resistance to sunitinib.
透明细胞肾细胞癌（ccRCC）的治疗仍然具有挑战性。趋化因子对癌细胞的增殖和转移有影响。目的是鉴定趋化因子相关基因并构建ccRCC的预后模型。
从癌症基因组图谱计划（TCGA）和GEO数据库获取批量转录组数据（n = 531）、单细胞RNA测序（scRNA-seq）数据集GSE159115以及其他验证队列。所有聚类分析均通过Seurat R包进行。进行了基因集富集分析（GSEA）、免疫浸润分析、单核苷酸变异（SNV）分析以及免疫治疗/化疗的预测反应分析。培养786-O和A498细胞系并将其应用于CCK-8、蛋白质免疫印迹和逆转录定量聚合酶链反应（RT-qPCR）试剂盒。
采用单因素Cox分析筛选出与生存相关的趋化因子相关基因。鉴定出锌指蛋白2（ZIC2）、小跨膜蛋白24（SMIM24）、Ⅶ型胶原α1链（COL7A1）、胰岛素样生长因子2结合蛋白3（IGF2BP3）、肌醇三磷酸激酶A（ITPKA）、含血小板反应蛋白基序的解聚蛋白样金属蛋白酶14（ADAMTS14）、细胞色素P450 3A7（CYP3A7）和极光激酶B（AURKB）并用于构建预后模型。在每个数据集中，高危组的预后比低危组差。高危组中记忆性CD8 + T细胞、巨噬细胞和记忆性B细胞较高，而低危组中嗜碱性粒细胞的含量较高。硼替佐米_1191、放线菌素D_1911、多西他赛_1007和达泊林_1248对高危组比低危组更敏感。此外，我们发现IGF2BP3在786-O和A498细胞系中对舒尼替尼的耐药性均显著升高。敲低IGF2BP3可显著降低ccRCC细胞的迁移和活力。
我们的研究基于ccRCC患者的综合转录图谱得出了一种新的趋化因子相关基因预后模型，揭示了肿瘤微环境对ccRCC生物学和免疫治疗反应的重大影响。我们将IGF2BP3鉴定为调节ccRCC对舒尼替尼耐药性的关键调节因子。
