Abstract
BackgroundClear 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.MethodsThe 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.ResultsNDUFA4L2 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.DiscussionNDUFA4L2 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.
Highlights
Renal cell carcinoma (RCC) is the third most common urological cancer with the highest mortality rate (Bukowski, 2009; Yang et al, 2010)
Our study provided potential mechanisms by which NDUFA4L2 affected Clear cell renal cell carcinoma (ccRCC) occurrence and progression
Analysis results in The Cancer Genome Atlas (TCGA) dataset further validated that the expression level of NDUFA4L2 was abnormally upregulated in ccRCC tissues compared with normal tissues and matched adjacent nontumor tissues (Fig. 1C)
Summary
Renal cell carcinoma (RCC) is the third most common urological cancer with the highest mortality rate (Bukowski, 2009; Yang et al, 2010). It was reported that NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) was highly expressed at both mRNA and protein levels in ccRCC samples but undetectable in normal kidney tissue samples. NDUFA4L2 mRNA expression level correlated with tumor stage and overall survival (Minton et al, 2016), and overexpression of NDUFA4L2 was reported to associate with poor prognosis in ccRCC patients (Lv et al, 2016). The underlying mechanism by which NDUFA4L2 exerted function and NDUFA4L2 expression level was upregulated need to be further investigated. The correlation between expression level of NDUFA4L2 and cell proliferation/apoptosis was explored by Gene Set Enrichment Analysis (GSEA). NDUFA4L2 was verified to be overexpressed in ccRCC tissues and its expression level was increased as the American Joint Committee on Cancer (AJCC) stage progressed. 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
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