A major subtype of renal cancer is clear cell renal cell carcinoma (ccRCC). Krüppel-like factor 3 (KLF3) dysfunction is also revealed leading to poor prognosis in multiple cancer types. However, dysregulation and molecular dynamics of KLF3 underlying ccRCC progression still remains elusive. Here KLF3 gene and protein expressions in ccRCC were explored using data cohorts from The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), Clinical Proteomic Tumor Analysis Consortium (CPTAC) and verified them in our patient cohort. Correlations of KLF3 expression with clinicopathological features, epigenetic modification, and immune microenvironment characteristics were further investigated. KLF3 was significantly down-regulated expressed in ccRCC tissues compared to adjacent normal controls. Adverse pathological parameters and poor prognosis were associated with lower expression of KLF3. Mechanically, KLF3 regulation was mainly attributed to CpG island methylation. KLF3-high expression subgroup was significantly enriched in cell signaling pathways most associated with EMT markers, angiogenesis, inflammatory response, apoptosis, TGF-β, degradation of ECM, G2M checkpoint, and PI3K-AKT-mTOR. Based on GDSC database, KLF3 upregulation was identified to be associated with higher sensitivities towards PI3K-Akt-mTOR pathway inhibitors such as PI-103, PIK-93, and OSI-027. In addition, patients with down-regulated KLF3 expressions were found more sensitive towards Trametinib, Cetuximab, and Erlotinib. Collectively, our findings suggest that KLF3 may act as a suitable biomarker for prognosis prediction, tumor microenvironment (TME) phenotype identification, thereby helping ccRCC patients to make better therapeutic decisions.

中文翻译：

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透明细胞肾细胞癌中 Krüppel 样因子 3 (KLF3) 的分子表达及其预后意义

肾癌的一个主要亚型是透明细胞肾细胞癌（ccRCC）。Krüppel 样因子 3 (KLF3) 功能障碍也被发现会导致多种癌症类型的预后不良。然而，ccRCC 进展背后的 KLF3 失调和分子动力学仍然难以捉摸。这里使用来自癌症基因组图谱 (TCGA)、人类蛋白质图谱 (HPA)、临床蛋白质组学肿瘤分析联盟 (CPTAC) 的数据队列探索了 ccRCC 中的 KLF3 基因和蛋白表达，并在我们的患者队列中进行了验证。进一步研究了KLF3表达与临床病理特征、表观遗传修饰和免疫微环境特征的相关性。与邻近的正常对照相比，KLF3 在 ccRCC 组织中的表达显着下调。不良病理参数和不良预后与 KLF3 表达较低相关。从机械角度来看，KLF3 调控主要归因于 CpG 岛甲基化。KLF3 高表达亚组显着富集与 EMT 标志物、血管生成、炎症反应、细胞凋亡、TGF-β、ECM 降解、G2M 检查点和 PI3K-AKT-mTOR 最相关的细胞信号通路。根据 GDSC 数据库，KLF3 上调被确定与对 PI3K-Akt-mTOR 通路抑制剂（如 PI-103、PIK-93 和 OSI-027）的更高敏感性相关。此外，KLF3 表达下调的患者对 Trametinib、西妥昔单抗和厄洛替尼更敏感。总的来说，我们的研究结果表明，KLF3 可能作为预后预测、肿瘤微环境 (TME) 表型识别的合适生物标志物，从而帮助 ccRCC 患者做出更好的治疗决策。