NDUFA4L2 is associated with clear cell renal cell carcinoma malignancy and is regulated by ELK1.
NDUFA4L2 is associated with clear cell renal cell carcinoma malignancy and is regulated by ELK1.
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NDUFA4L2 与透明细胞肾细胞癌恶性肿瘤相关，并受 ELK1 调节
作者：
Wang L;Peng Z;Wang K;Qi Y;Yang Y;Zhang Y;An X;Luo S;Zheng J
透明细胞肾细胞癌（Clear cell renal cell carcinoma，ccRCC）是成人肾脏最常见和最致命的癌症。然而，其发病机制至今尚未完全清楚，这阻碍了ccRCC治疗的发展。发现NADH脱氢酶（泛醌）1 α亚复合物4-样2（NDUFA 4L 2）上调，并在ccRCC中发挥重要作用。我们的目的是进一步研究NDUFA 4L 2发挥功能和其表达水平上调的潜在机制。方法利用基因表达谱（GEO）和肿瘤基因组图谱（TCGA）数据库，验证NDUFA 4L 2在肾细胞癌组织中表达水平的变化。通过基因集富集分析（Gene Set Enrichment Analysis，GSEA）探讨NDUFA 4L 2表达水平与细胞增殖/凋亡的相关性。构建了NDUFA 4L 2的蛋白质相互作用（PPI）网络。利用基因本体论（GO）和京都基因与基因组百科全书（KEGG）途径分析NDUFA 4 L2的生物学过程和相关通路。通过相关性分析寻找临床标本中能诱导NDUFA 4L 2表达的转录因子，并通过敲低实验验证其对NDUFA 4L 2表达的调控作用。结果NDUFA 4L 2在肾细胞癌组织中高表达，其表达水平随着美国癌症联合委员会（AJCC）分期的进展而升高。高NDUFA 4L 2水平预测ccRCC患者的不良预后，并与增强的细胞增殖和抗凋亡相关。NDUFA 4L 2可能与14种肿瘤相关蛋白相互作用，参与生长和死亡过程，并参与ccRCC相关途径，如胰岛素样生长因子1（IGF-1）、哺乳动物雷帕霉素靶蛋白（mTOR）和磷酸肌醇3激酶丝氨酸/苏氨酸蛋白激酶（PI 3 K/AKT）。在ccRCC组织中，ETS结构域蛋白ELK 1的表达水平与NDUFA 4L 2的表达水平呈正相关，ELK 1可调节NDUFA 4L 2在ccRCC细胞中的表达。讨论NDUFA 4L 2上调与ccRCC恶性相关。在ccRCC细胞中，NDUFA 4L 2表达受ELK 1调节。我们的研究提供了NDUFA 4L 2影响ccRCC发生和进展的潜在机制。
Background Clear cell renal cell carcinoma (ccRCC) is the most common and lethal cancer of the adult kidney. However, its pathogenesis has not been fully understood till now, which hinders the therapeutic development of ccRCC. NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) was found to be upregulated and play an important role in ccRCC. We aimed to further investigate the underlying mechanisms by which NDUFA4L2 exerted function and its expression level was upregulated. Methods The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data were mined to verify the change of NDUFA4L2 expression level in ccRCC tissues. The correlation between expression level of NDUFA4L2 and cell proliferation/apoptosis was explored by Gene Set Enrichment Analysis (GSEA). Protein-protein interaction (PPI) network of NDUFA4L2 was constructed. Biological process and involved pathways of NDUFA4L2 were analyzed by gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The transcription factors (TFs) which can induce the expression of NDUFA4L2 were explored in clinical samples by correlation analysis and its regulation on the expression of NDUFA4L2 was verified by knockdown experiment. Results NDUFA4L2 was verified to be overexpressed in ccRCC tissues and its expression level was increased accordingly as the American Joint Committee on Cancer (AJCC) stage progressed. A high NDUFA4L2 level predicted the poor prognosis of ccRCC patients and correlated with enhanced cell proliferation and anti-apoptosis. NDUFA4L2 may interact with 14 tumor-related proteins, participate in growth and death processes and be involved in ccRCC-related pathways, such as insulin-like growth factor 1 (IGF-1), mammalian target of Rapamycin (mTOR) and phosphoinositide 3 kinase serine/threonine protein kinase (PI3K/AKT). ETS domain-containing protein ELK1 level positively correlated with the level of NDUFA4L2 in ccRCC tissues and ELK1 could regulate the expression of NDUFA4L2 in ccRCC cells. Discussion NDUFA4L2 upregulation was associated with ccRCC malignancy. NDUFA4L2 expression was regulated by ELK1 in ccRCC cells. Our study provided potential mechanisms by which NDUFA4L2 affected ccRCC occurrence and progression.