Signaling Pathways in Clear Cell Renal Cell Carcinoma and Candidate Drugs Unveiled through Transcriptomic Network Analysis of Hub Genes
Abstract
:1. Introduction
2. Materials and Methods
2.1. Data Retrieval and Preliminary Processing
2.2. Weighted Gene Co-Expression Network Analysis (WGCNA)
2.2.1. Determining the Optimal Soft-Thresholding Power for Scale-Free Network
2.2.2. Construction of Networks and Identification of Modules
2.3. Module Preservation Analysis
2.4. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathways Analysis
2.5. Protein–Protein Interaction (PPI) Network Analysis
2.6. Survival Analysis of Hub Genes
2.7. Drug Repurposing Analysis
3. Results
3.1. Weighted Gene Co-Expression Network Analysis (WGCNA)
3.1.1. Scale-Free Network Analysis of the ccRCC Datasets
3.1.2. Network Construction and Module Identification
3.2. Module Preservation Analysis
3.3. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathways Analyses
3.4. Protein–Protein Interaction (PPI) Networks and Hub Genes Analysis
3.5. Survival Analysis
3.6. Drug Repurposing Analysis
4. Discussion
4.1. Gene Expression Modules and Pathway Analysis across the Datasets
4.2. Module Key Hub Genes and Their Protein Functions
4.2.1. Involvement of Hub Genes in Inflammation-Related Pathways Associated with ccRCC
4.2.2. Protein Chaperones and Epigenetic Regulators in Inflammation and Tumor Development in ccRCC
4.2.3. Metabolic Reprogramming in ccRCC
4.3. Viral Infections Associated with ccRCC
4.4. Drug Repurposing Based on Gene Signatures
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
KEGG | Term | Count | p-Value |
---|---|---|---|
Blue | Pathways in cancer | 68 | 1.27 × 10−5 |
Viral carcinogenesis | 33 | 5.01 × 10−5 | |
Ras signaling pathway | 29 | 0.01091 | |
TGF-β signaling pathway | 18 | 0.002582 | |
Renal cell carcinoma | 16 | 1.63 × 10−4 | |
Brown | Pathways in cancer | 65 | 2.69 × 10−6 |
PI3K-Akt signaling pathway | 46 | 3.74 × 10−5 | |
MAPK signaling pathway | 37 | 4.46 × 10−4 | |
Hippo signaling pathway | 23 | 7.59 × 10−4 | |
Renal cell carcinoma | 11 | 0.017668 | |
Red | Pathways in cancer | 66 | 2.69 × 10−6 |
MAPK signaling pathway | 43 | 1.50 × 10−6 | |
PI3K-Akt signaling pathway | 41 | 5.81 × 10−4 | |
Ras signaling pathway | 30 | 7.19 × 10−4 | |
HIF-1 signaling pathway | 17 | 0.003199 |
KEGG | Term | Count | p-Value |
---|---|---|---|
Turquoise | Pathways in cancer | 63 | 3.51 × 10−6 |
PI3K-Akt signaling pathway | 47 | 7.03 × 10−6 | |
MAPK signaling pathway | 37 | 2.28 × 10−4 | |
Hippo signaling pathway | 21 | 0.002751 | |
mTOR signaling pathway | 19 | 0.013614 | |
Yellow | Metabolic pathways | 123 | 0.029441 |
Pathways in cancer | 60 | 6.99 × 10−5 | |
EGFR tyrosine kinase inhibitor resistance | 14 | 2.31 × 10−3 | |
NF-kB signaling pathway | 14 | 0.022381 | |
HIF-1 signaling pathway | 14 | 0.029444 | |
Green | Pathways in cancer | 58 | 5.47 × 10−4 |
Human papillomavirus infection | 35 | 0.013714 | |
Human cytomegalovirus infection | 30 | 8.63 × 10−4 | |
Viral carcinogenesis | 24 | 0.014283 | |
Viral myocarditis | 16 | 5.64 × 10−5 |
Category | Term | Count | p-Value |
---|---|---|---|
BP | GO:0045944~positive regulation of transcription by RNA polymerase II | 152 | 2.35 × 10−14 |
GO:0045893~positive regulation of DNA-templated transcription | 94 | 4.34 × 10−11 | |
GO:0006338~chromatin remodeling | 69 | 3.39 × 10−17 | |
GO:0000398~mRNA splicing, via spliceosome | 47 | 2.93 × 10−14 | |
GO:0008380~RNA splicing | 38 | 5.65 × 10−9 | |
CC | GO:0005829~cytosol | 656 | 6.62 × 10−79 |
GO:0005634~nucleus | 627 | 2.76 × 10−50 | |
GO:0005737~cytoplasm | 550 | 9.12 × 10−34 | |
GO:0005654~nucleoplasm | 544 | 2.40 × 10−85 | |
GO:0000785~chromatin | 120 | 1.89 × 10−8 | |
MF | GO:0005515~protein binding | 1116 | 7.48 × 10−69 |
GO:0003723~RNA binding | 248 | 7.34 × 10−46 | |
GO:0042802~identical protein binding | 169 | 3.16 × 10−7 | |
GO:0061629~RNA polymerase II-specific DNA-binding transcription factor binding | 31 | 4.44 × 10−6 | |
GO:0140297~DNA-binding transcription factor binding | 30 | 3.22 × 10−6 |
Category | Term | Count | p-Value |
---|---|---|---|
BP | GO:0045944~positive regulation of transcription by RNA polymerase II | 115 | 4.74 × 10−9 |
GO:0007165~signal transduction | 114 | 4.41 × 10−9 | |
GO:0000122~negative regulation of transcription by RNA polymerase II | 81 | 2.91 × 10−5 | |
GO:0045893~positive regulation of DNA-templated transcription | 68 | 2.60 × 10−6 | |
GO:0008380~RNA splicing | 38 | 5.65 × 10−9 | |
CC | GO:0005886~plasma membrane | 389 | 5.98 × 10−14 |
GO:0005829~cytosol | 363 | 2.61 × 10−8 | |
GO:0005737~cytoplasm | 345 | 6.44 × 10−5 | |
GO:0005654~nucleoplasm | 245 | 5.81 × 10−4 | |
GO:0070062~extracellular exosome | 188 | 1.76 × 10−12 | |
MF | GO:0005515~protein binding | 790 | 8.86 × 10−14 |
GO:0042802~identical protein binding | 133 | 2.09 × 10−5 | |
GO:0004672~protein kinase activity | 27 | 3.93 × 10−3 | |
GO:0005178~integrin binding | 22 | 1.55 × 10−4 | |
GO:0004713~protein tyrosine kinase activity | 17 | 1.26 × 10−4 |
Category | Term | Count | p-Value |
---|---|---|---|
BP | GO:0045944~positive regulation of transcription by RNA polymerase II | 118 | 7.69 × 10−11 |
GO:0007165~signal transduction | 103 | 7.45 × 10−7 | |
GO:0030154~cell differentiation | 58 | 3.70 × 10−5 | |
GO:0045893~positive regulation of DNA-templated transcription | 56 | 0.0013 | |
GO:0008284~positive regulation of cell population proliferation | 50 | 1.10 × 10−5 | |
CC | GO:0005737~cytoplasm | 368 | 1.72 × 10−9 |
GO:0005829~cytosol | 351 | 1.53 × 10−7 | |
GO:0005654~nucleoplasm | 240 | 5.72 × 10−4 | |
GO:0048471~perinuclear region of cytoplasm | 54 | 6.57 × 10−3 | |
GO:0032991~protein-containing complex | 49 | 8.41 × 10−3 | |
MF | GO:0005515~protein binding | 747 | 4.49 × 10−8 |
GO:0042802~identical protein binding | 129 | 4.40 × 10−5 | |
GO:0106310~protein serine kinase activity | 34 | 1.76 × 10−3 | |
GO:0045296~cadherin binding | 33 | 8.03 × 10−4 | |
GO:0043565~sequence-specific DNA binding | 32 | 1.00 × 10−4 |
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Accession No. | GSE53757 | GSE22541 | GSE66272 | GSE73731 |
---|---|---|---|---|
Condition | ccRCC Stage 1 (S1) | ccRCC Stage 2 (S2) | ccRCC Stage 3 (S3) | ccRCC Stage 4 (S4) |
Type | Expression Profiling by Array | |||
Platform | GPL570—HG-U133 Plus 2 Affymetrix Human Genome U133 Plus 2.0 Array | |||
Source | Primary Tumor Samples | |||
No. of Samples | 24 | 21 | 27 | 44 |
Genes | Drug | Mechanism | Tau | FDR | |
---|---|---|---|---|---|
Upregulated | ATM, CDC4, GSK3B, ITGA2B, MAPK8, MED1, PPARG, RPL5, CD44, HNRNPC, BCL2, CALML3, EGFR, GRB2, HDAC1, HSP90AA1, INS, PRKACG, SOX2, SRC, SMAD3, MAPK1, and TGFB1 | Ziprasidone | Dopamine receptor antagonist, Serotonin receptor antagonist | −99.0039 | 0.00884 |
Etazolate | Phosphodiesterase inhibitor | −98.9247 | 0.00207 | ||
Trequinsin | Phosphodiesterase inhibitor | −97.5632 | 0.00557 | ||
Dicycloverine | Acetylcholine receptor antagonist | −97.26467 | 0.00936 | ||
Decitabine | DNA methyltransferase inhibitor | −96.3448 | 0.00267 | ||
Downregulated | PTK2, BDNF, CREBBP, DLG4, EP300, H3C12, and ESR1 | Fentiazac | Cyclooxygenase inhibitor | −99.6497 | 0.001254 |
Asenapine | Dopamine receptor antagonist, serotonin receptor antagonist | −99.2415 | 0.007037 | ||
Ku-60019 | ATM kinase inhibitor | −99.1959 | 0.007115 | ||
Fr-180204 | MAP kinase inhibitor | −98.2394 | 0.000190 | ||
Niacin | NAD precursor, vitamin B | −98.2211 | 0.002544 |
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Suratos, K.S.; Orda, M.A.; Tsai, P.-W.; Tayo, L.L. Signaling Pathways in Clear Cell Renal Cell Carcinoma and Candidate Drugs Unveiled through Transcriptomic Network Analysis of Hub Genes. Appl. Sci. 2024, 14, 8768. https://doi.org/10.3390/app14198768
Suratos KS, Orda MA, Tsai P-W, Tayo LL. Signaling Pathways in Clear Cell Renal Cell Carcinoma and Candidate Drugs Unveiled through Transcriptomic Network Analysis of Hub Genes. Applied Sciences. 2024; 14(19):8768. https://doi.org/10.3390/app14198768
Chicago/Turabian StyleSuratos, Khyle S., Marco A. Orda, Po-Wei Tsai, and Lemmuel L. Tayo. 2024. "Signaling Pathways in Clear Cell Renal Cell Carcinoma and Candidate Drugs Unveiled through Transcriptomic Network Analysis of Hub Genes" Applied Sciences 14, no. 19: 8768. https://doi.org/10.3390/app14198768