J Cancer 2019; 10(27):6779-6791. doi:10.7150/jca.35223

Research Paper

Three novel hub genes and their clinical significance in clear cell renal cell carcinoma

He Xiao1,2*, Ping Chen2*, Guang Zeng2,3, Deqiang Xu2, Xinghuan Wang2, Xinhua Zhang2✉

1. Urological Surgery, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430017, China
2. Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, P.R. China
3. Biomedical Engineering, Stony Brook University, New York 11790
*These authors have contributed equally to this work.

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Citation:
Xiao H, Chen P, Zeng G, Xu D, Wang X, Zhang X. Three novel hub genes and their clinical significance in clear cell renal cell carcinoma. J Cancer 2019; 10(27):6779-6791. doi:10.7150/jca.35223. Available from http://www.jcancer.org/v10p6779.htm

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Abstract

Purpose. To investigate the association of biomarkers correlated with clinical stages and survival of clear cell renal cell carcinoma (ccRCC).

Methods. The GSE36895 dataset was downloaded and differentially expressed or methylated genes were analyzed. Hub genes were identified with weighted gene co-expression network analysis (WGCNA) and protein-protein interaction network (PPI), and validated with TCGA database and our own tissues. The biological processes of hub genes were further explored by functional enrichment analysis. Survival analyses were also performed. The underlying mechanisms for ccRCC development were detected with Gene set enrichment analyses.

Results. A total of 1624 differentially expressed genes were analyzed by WGCNA and 6 co-expressed gene modules were identified. Three hub genes (EHHADH, ACADM and AGXT2) were met the criterion of both WGCNA and PPI networks analysis, which showed highest negative association with pathological T stage (r = - 0.45, p = 0.01) and tumor grade (r = - 0.45, p = 0.01). The downregulation of these hub genes was validated with using both TCGA database and samples harvested at our institute The biological processes that hub genes involved, such as metabolic process (p = 9.63E - 09), oxidation-reduction process (p = 1.05E - 08) and oxidoreductase activity (p = 1.72E - 04), were revealed. Survival analysis showed a higher expression or lower methylation of these hub genes, a longer survival of ccRCC patients. ccRCC samples with higher expression of hub genes were enriched in gene sets correlated with signaling like biosynthesis of unsaturated fatty acids, butanoate metabolism, and PPAR signaling pathway.

Conclusions. We identified three novel tumor suppressors associated with pathological T stage and overall survival of ccRCC. They might be potential as individualized therapeutic targets and diagnostic biomarkers for ccRCC.

Keywords: weighted gene co-expression network analysis (WGCNA), clear cell renal cell carcinoma (ccRCC), survival, prognosis, biomarkers