Identification of Key Biomarkers in Bladder Cancer: Evidence from a Bioinformatics Analysis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Acquisition of Microarray Data
2.2. Identification of DEGs
2.3. GO and KEGG Analyses of DEGs
2.4. Protein‒Protein Interaction (PPI) Network Analysis
2.5. Clinical Data Analysis and Oncomine Analysis
3. Results
3.1. Identification of DEGs in BCa
3.2. GO and KEGG Enrichment Analyses of DEGs
3.2.1. GO Biological Process (BP)
3.2.2. GO Cellular Component (CC)
3.2.3. GO Molecular Function (MF)
3.2.4. KEGG Pathway Analysis
3.3. PPI Network Analysis
3.4. Hub Gene Selection and Analysis
3.5. Clinical Analysis and Oncomine Analysis Outcomes of Hub Genes
4. Discussion
4.1. Biological Progression Potentially Associated with BCa
4.2. The Hub Genes Are Potentially Associated with the Clinical Outcomes
4.3. The Hub Genes Potentially Associated with the Clinical Prognosis in Previous Research
4.4. Major Findings of the Recent Study
- (i)
- TPM1, CRYAB, and CASQ2 were significantly downregulated in BCa, while the remaining 11 hub genes were significantly upregulated.
- (ii)
- All hub genes showed a significant difference between the lymph node metastasis status and noncancerous tissues. In particular, UBE2C, CDC20, MAD2L1, TPM1, and CASQ2 potentially play a pivotal role in lymph node metastasis.
- (iii)
- CCNB1, KPNA2, TPM1, CASQ2, and CRYAB were correlated with prognosis in overall survival (OS) analysis, while CCNA2, KIF11, KIF20A, CASQ2, and CRYAB were correlated with disease-free survival (DFS). Interestingly, CRYAB and CASQ2 were correlated with both OS and DFS.
- (iv)
- We here report evidence for an up to now unrecognized possible role of CASQ2 in cancer and for CRYAB in bladder cancer. In combination with the results from the HPA, our study suggests that CRYAB would be a candidate biomarker in BCa, followed by CASQ2, TPM1, and KPNA2.
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
BCa | Bladder cancer |
GEO | Gene Expression Omnibus |
TCGA-BLCA | Cancer Genome Atlas Bladder Cancer |
GO | Gene ontology |
KEGG | Kyoto Encyclopedia of Genes and Genomes |
PPI | Protein‒protein interaction |
FC | Fold change |
RLE | Relative log expression |
OS | Overall survival |
DFS | Disease-free survival |
HJURP | Holliday junction recognition protein |
TAGLN | Transgelin |
PLAU | Urokinase |
SLMAP | Sarcolemmal membrane-associated protein |
NMIBC | Non-muscle-invasive bladder cancer |
MIBC | Muscle-invasive bladder cancer |
DEGs | Differentially expressed genes |
MCODE | Molecular complex detection |
GEPIA | Gene expression profiling interactive analysis |
BP | Biological process |
CC | Cellular component |
MF | Molecular function |
cGMP-PKG | Cyclic guanosine monophosphate-dependent protein kinase |
cAMP | Cyclic adenosine monophosphate |
FPKM | Fragments per kilobase million |
TPM | Transcripts per million |
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Dataset | Number of Noncancerous Bladder Tissue Samples | Number of Cancer Tissue Samples | Number of DEGs | Platform | Manufacturer of Platform |
---|---|---|---|---|---|
GSE27448 | 5 | 10 | 4701 | GPL2895 | GE Healthcare |
GSE52519 | 3 | 9 | 742 | GPL16884 | JPT Peptide Technology |
GSE61615 | 2 | 2 | 736 | GPL14550 | Agilent Technologies |
GSE76211 | 3 | 3 | 658 | GPL17586 | Affymetrix |
GSE100926 | 3 | 3 | 194 | GPL16956 | Agilent Technologies |
Gene Symbol | Other Names | Full Name | Role of Genes | Putative or Observed Effect |
---|---|---|---|---|
CDK1 | CDC2, CDC28A, P34CDC2 | Cyclin-dependent kinase 1 | Oncogene | Overexpression in BCa; Activating CDK1 facilitates the proliferation and invasion of BCa. [23] |
CCNB1 | cyclin B1 | CCNB | Oncogene | Increased expression in BCa; Regulating BCa through the FoxM1/CCNB1 pathway, correlates with poor prognosis. [24] |
KIF11 | kinesin family member 11 | EG5; HKSP; KNSL1; MCLMR; TRIP5 | Oncogene | Overexpression in BCa; Predicted to be Oncogene. [25] |
CCNA2 | cyclin A2 | CCN1; CCNA | Oncogene | Over expression in BCa; Activity of CCNA2 regulated the EMT via ROCK/AKT/β-catenin/SNAIL pathway to influence the prognosis of BCa. [26] |
UBE2C | ubiquitin conjugating enzyme E2 C | UBCH10; dJ447F3.2 | Oncogene | High expression in BCa; Activating UBE2C induced progression and correlates with poor survival. [27,28] |
CDC20 | cell division cycle 20 | CDC20A; p55CDC; bA276H19.3 | Oncogene | Increased expression in BCa; Activating CDC20 increased carcinogenesis and correlates with poor survival in BCa. [29] |
MAD2L1 | mitotic arrest deficient 2 like 1 | MAD2; HSMAD2 | Oncogene | Overexpression in BCa; Activating MAD2 was associated with incidence of recurrence and progression of BCa. [30] |
KIF2C | kinesin family member 2C | MCAK; CT139; KNSL6 | Oncogene | Overexpression of KIF2C was confirmed in BCa from rat model. [31] |
AURKA | aurora kinase A | AIK; ARK1; AURA; BTAK; STK6; STK7; STK15; PPP1R47 | Oncogene | Highly expression in BCa; Activating AURKA is associated with poor prognosis, tumor stage and grade. [32,33] |
KIF20A | kinesin family member 20A | MKLP2; RAB6KIFL | Oncogene | Over expression in BCa; KIF20A was associated with the development of BCa and correlated with poor survival. [34] |
KPNA2 | karyopherin subunit alpha 2 | QIP2; RCH1; IPOA1; SRP1alpha; SRP1-alpha | Oncogene | Increased expression in BCa; Activation of KPNA2 defines poor prognosis in BCa. [35,36] |
TPM1 | tropomyosin 1 | CMH3; TMSA; CMD1Y; LVNC9; C15orf13; | Tumor suppressor | Downregulated in BCa; Activating TPM1 inhibited the proliferation and promoted the apoptosis of Bladder tumor cells. [37,38] |
CASQ2 | calsequestrin 2 | PDIB2 | Disease-related gene | Reduced in BCa in present study; Predicted to be tumor suppressor; No study of CASQ2 reported in BCa. [39] |
CRYAB | crystallin alpha B | MFM2; CRYA2; CTPP2; HSPB5; CMD1II; CTRCT16; | Cancer-related gene | Decreased expression in BCa in present study; Enforced activation of CRYAB correlated to poor prognosis of lung cancer and other tumors [40]; No study of CRYAB reported in BCa. |
Hub Genes | Reference | ||
---|---|---|---|
Upregulated | Downregulated | Regulation not Specified | (Databases Used) |
AURKA *, CCNA2 *, CCNE1#, CDC20 *, BCL3#, CEP55 *, DCUN1D1#, FGFR1OP#, HMMR *, MAP3K8#, MYB#, PTG1#, VEGFA# | DUSP26#, MEIS1 * | Han et al. [48] (GSE52519) | |
CDC20 * | ACTA#, DCN#, MYH11 *, TPM1 *, VIM#, TGFB3# | Hu et al. [49] (GSE13507, TCGA-BLCA) | |
ITGA7#, GRB14#, CDC20 *, PSMB1#, POLR2F/2H#, RPS14/15# | Jia et al. [50] (GSE27448) | ||
EME1#, AKAP9#, ZNF91#, OARD3#, STAG2#, ZFP36L2#, METTL3#, POLR3#, MUC7# | Han et al. [51] (TCGA-BLCA) | ||
DSN1#, KNTC1 *, CDK1 *, CENPM#, HIST1H2BJ#, EZH2 *, CENPF *, RAD51#, BRCA1#, EXO1# | Jiang and Yuan [52] (Circular RNA Interactome database; TCGA) | ||
CDH1#, DDOST#, CASP8#, DHX15#, PTRF@ | GNG4#, ADCY9#, NPY#, ADRA2B#, PENK# | Zhang et al. [53] (GSE3167, GSE65635, GSE33510) | |
TOP2A *, CDC20 *, UBE2C *, CCNB1 *, CCNB2 *, VEGFA#, AURKB *, AURKA *, CEP55 * | ACTA2# | Gao et al. [54] (GSE7476, GSE13507, GSE37815, GSE65635) |
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Zhang, C.; Berndt-Paetz, M.; Neuhaus, J. Identification of Key Biomarkers in Bladder Cancer: Evidence from a Bioinformatics Analysis. Diagnostics 2020, 10, 66. https://doi.org/10.3390/diagnostics10020066
Zhang C, Berndt-Paetz M, Neuhaus J. Identification of Key Biomarkers in Bladder Cancer: Evidence from a Bioinformatics Analysis. Diagnostics. 2020; 10(2):66. https://doi.org/10.3390/diagnostics10020066
Chicago/Turabian StyleZhang, Chuan, Mandy Berndt-Paetz, and Jochen Neuhaus. 2020. "Identification of Key Biomarkers in Bladder Cancer: Evidence from a Bioinformatics Analysis" Diagnostics 10, no. 2: 66. https://doi.org/10.3390/diagnostics10020066