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. 2016:2016:4149608.
doi: 10.1155/2016/4149608. Epub 2016 Feb 29.

Network Biomarkers of Bladder Cancer Based on a Genome-Wide Genetic and Epigenetic Network Derived from Next-Generation Sequencing Data

Cheng-Wei Li  1 , Bor-Sen Chen  1
Affiliations

Network Biomarkers of Bladder Cancer Based on a Genome-Wide Genetic and Epigenetic Network Derived from Next-Generation Sequencing Data

Cheng-Wei Li et al. Dis Markers. 2016.

Abstract

Epigenetic and microRNA (miRNA) regulation are associated with carcinogenesis and the development of cancer. By using the available omics data, including those from next-generation sequencing (NGS), genome-wide methylation profiling, candidate integrated genetic and epigenetic network (IGEN) analysis, and drug response genome-wide microarray analysis, we constructed an IGEN system based on three coupling regression models that characterize protein-protein interaction networks (PPINs), gene regulatory networks (GRNs), miRNA regulatory networks (MRNs), and epigenetic regulatory networks (ERNs). By applying system identification method and principal genome-wide network projection (PGNP) to IGEN analysis, we identified the core network biomarkers to investigate bladder carcinogenic mechanisms and design multiple drug combinations for treating bladder cancer with minimal side-effects. The progression of DNA repair and cell proliferation in stage 1 bladder cancer ultimately results not only in the derepression of miR-200a and miR-200b but also in the regulation of the TNF pathway to metastasis-related genes or proteins, cell proliferation, and DNA repair in stage 4 bladder cancer. We designed a multiple drug combination comprising gefitinib, estradiol, yohimbine, and fulvestrant for treating stage 1 bladder cancer with minimal side-effects, and another multiple drug combination comprising gefitinib, estradiol, chlorpromazine, and LY294002 for treating stage 4 bladder cancer with minimal side-effects.

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Figures

Figure 1
Figure 1
Flowchart of the proposed method for constructing the core network biomarkers and identifying bladder carcinogenesis mechanisms.
Figure 2
Figure 2
Flowchart of the proposed methodology to identify the IGENs for normal bladder cells, and stage 1 and 4 bladder cancer cells.
Figure 3
Figure 3
Comparison of genetic and epigenetic alterations and connection changes in the core network biomarkers of bladder carcinogenesis between normal bladder cells and stage 1 bladder cancer cells. Red, blue, and black gene/miRNA symbols represent the highly expressed genes, the suppressed genes, and the nondifferentially expressed genes in stage 1 bladder cancer cells, respectively, compared with normal bladder cells. Dashed and solid lines denote the identified connections in normal and cancerous cells, respectively. The identified connections of the core network biomarkers do not exist in normal bladder cells only. Bold lines indicate the high regulatory or interaction parameters, that is, a ij, c li, and d jk, identified in the stochastic regression models (1)–(3) of the IGEN. The bold proteins, including RARRES3, TUBA1C, PSMD8, HSPA1B, RPS20, CALR, PAAF1, and KPNA2, were the identified core network biomarkers. The major factors, including downregulated miR1-2, the aging-related proteins, HSP90B1, CALR, HSPA5, PDIA3, RPN1, and ECT2, the smoking-related proteins, HUWE1, HSPA5, and ECT2, and the epigenetic regulation of ENO1, HSP90B1, CALR, and PDIA3, lead to the progression from normal bladder cells to stage 1 bladder cancer cells through the SUP and ER signaling pathways.
Figure 4
Figure 4
Comparison of genetic and epigenetic alterations and connection changes in the core network biomarkers of bladder carcinogenesis between stage 1 and stage 4 bladder cancer cells. Red, blue, and black gene/miRNA symbols represent the highly expressed genes, the suppressed genes, and the nondifferentially expressed genes in stage 4 bladder cancer cells, respectively, compared with stage 1 bladder cancer cells. Dashed, dash-dot, and solid lines denote the identified connections in stage 1 cancer cells, stage 4 cancer cells, and both stage 1 and 4 cancer cells, respectively. Bold lines indicate the high regulatory or interaction parameters, that is, a ij, c li, and d jk, identified in the stochastic regression models (1)–(3) of the IGEN. The bold proteins RARRES3, TUBA1C, PSMD8, HSPA1B, RPS20, CALR, PAAF1, and KPNA2 were the identified core network biomarkers. The smoking-related protein HSP90AA1 and DNA methylation of ECT2 mediate metastasis of bladder cancer.
Figure 5
Figure 5
Module network of the core network biomarkers in Figure 3 for investigating the bladder carcinogenic mechanisms from normal bladder cells to stage 1 bladder cancer cells. The notations of gene/miRNA symbols and line styles are the same as those in Figure 3. The activated TFs KPNA2, COPS5, PSMD12, and ECT2 play an important role in mediating the signal transduction of the SUP and ER pathways to activate cell proliferation and metastasis in stage 1 bladder cancer. The metastasis of the stage 1 bladder cancer is repressed by the activated miRNAs miR200a and miR200b.
Figure 6
Figure 6
Module network of the core network biomarkers in Figure 4 to investigate the bladder carcinogenic mechanisms from stage 1 to stage 4 bladder cancer cells. The notations of gene/miRNA symbols and line styles are the same as those in Figure 4. The activated DNA repair of bladder cancer cells leads to metastasis owing to the immortality of cancer cells. The activated JUN in the TNF pathway induces cell proliferation, DNA repair, and metastasis in stage 4 bladder cancer cells.
Figure 7
Figure 7
The carcinogenic mechanisms from normal to stage 1 bladder cancer cells (a), and from stage 1 to stage 4 bladder cancer cells (b). When the accumulated genetic mutations and epigenetic alterations lead to the dysregulation of the TNF pathway in inflammation, the accumulated misfolded proteins in the ER pathway induce cell proliferation in stage 1 bladder cancer (a). The regulations of ER and TNF pathways are adaptive to the accumulated genetic mutations and epigenetic alterations through the SUP pathway. The progression of DNA repair and cell proliferation in stage 1 bladder cancer ultimately results not only in the repression of miR200a and miR200b during metastasis, but also in the regulation of the TNF pathway to metastasis, cell proliferation, and DNA repair in stage 4 bladder cancer (b).
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