全面分析 MFN2 作为与肾透明细胞癌免疫细胞浸润相关的预后生物标志物。
Comprehensive analysis of MFN2 as a prognostic biomarker associated with immune cell infiltration in renal clear cell carcinoma.
机构信息
Department of Urology, the First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China.
Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.
出版信息
Int Immunopharmacol. 2022 Oct;111:109169. doi: 10.1016/j.intimp.2022.109169. Epub 2022 Aug 22.
BACKGROUND
Treatment of advanced kidney renal clear cell carcinoma (KIRC) remains challenging in clinic. The functional role and prognostic significance of MFN2 in KIRC are still unclear.
METHODS
In this study, we first performed a bioinformatic analysis to determine the expression level and prognostic value of MFN2 in KIRC using The Cancer Genome Atlas (TCGA) dataset, and then validated the MFN2 mRNA expression in our cohort of clinical tissue samples and cell lines of KIRC via RT-qPCR. Cox regression model was used to identify the independent prognostic factors. A nomogram was constructed to predict the prognosis of KIRC patients. Gene set enrichment analysis (GSEA) was performed to predict the involved functional pathways of MFN2 co-expressed genes. The association between MFN2 expression level and immune cell infiltration was assessed using the TIMER and the TIDISB databases. In addition, cell proliferation and migration abilities of two KIRC cell lines with MFN2 overexpression were evaluated by MTS and wound healing assays, respectively.
RESULTS
Downregulation of MFN2 was observed in KIRC tissues and cell lines compared to the normal controls. Kaplan-Meier curve analysis indicated an inferior survival outcomes in KIRC patients with lower MFN2 expression, uncovering the tumor-suppressive role of MFN2 in KIRC. Cox regression results showed that higher MFN2 expression was one of the independent protective factors in KIRC. Besides, function predictive analysis revealed that MFN2 co-expressed genes were enriched in the biological processes of energy metabolism and autophagy. Moreover, MFN2 expression was observed to be significantly associated with immune cell infiltration and a variety of markers of tumor infiltrating immune cells (TIICs) including multiple immune checkpoints in KIRC tissues. Finally, MFN2 overexpression significantly inhibited cell proliferation and migration abilities of two KIRC cell lines examined.
CONCLUSION
Generally, our data suggested that MFN2 may serve as a potential prognostic biomarker and therapeutic target in KIRC.
背景
晚期肾透明细胞癌（KIRC）的治疗仍然具有挑战性。MFN2 在 KIRC 中的功能作用和预后意义尚不清楚。
方法
本研究首先使用癌症基因组图谱（TCGA）数据集进行生物信息学分析，确定 MFN2 在 KIRC 中的表达水平和预后价值，然后通过 RT-qPCR 验证 KIRC 临床组织样本和细胞系中 MFN2 的 mRNA 表达。Cox 回归模型用于识别独立的预后因素。构建列线图预测 KIRC 患者的预后。进行基因集富集分析（GSEA）以预测 MFN2 共表达基因涉及的功能途径。使用 TIMER 和 TIDISB 数据库评估 MFN2 表达水平与免疫细胞浸润的相关性。此外，通过 MTS 和划痕愈合实验分别评估了两种过表达 MFN2 的 KIRC 细胞系的细胞增殖和迁移能力。
结果
与正常对照相比，KIRC 组织和细胞系中观察到 MFN2 的下调。Kaplan-Meier 曲线分析表明，MFN2 表达较低的 KIRC 患者生存结局较差，揭示了 MFN2 在 KIRC 中的肿瘤抑制作用。Cox 回归结果表明，较高的 MFN2 表达是 KIRC 的独立保护因素之一。此外，功能预测分析表明，MFN2 共表达基因富集在能量代谢和自噬等生物学过程中。此外，在 KIRC 组织中观察到 MFN2 表达与免疫细胞浸润以及多种肿瘤浸润免疫细胞（TIIC）标志物显著相关，包括多种免疫检查点。最后，MFN2 过表达显著抑制了两种 KIRC 细胞系的增殖和迁移能力。
结论
总的来说，我们的数据表明，MFN2 可能是 KIRC 潜在的预后生物标志物和治疗靶点。
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