The underlying molecular mechanism and potential drugs for treatment in papillary renal cell carcinoma: A study based on TCGA and Cmap datasets
- Authors:
- Published online on: February 14, 2019 https://doi.org/10.3892/or.2019.7014
- Pages: 2089-2102
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Copyright: © Pang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Papillary renal cell carcinoma (PRCC) is the second most prevalent subtype of renal cell carcinoma (RCC) and it represents 15–20% of all kidney neoplasms (1–4). Compared with patients with clear RCC (CCRCC), those with PRCC generally have a more favorable outcome following surgical treatment and these patients are less likely to exhibit distant metastasis and recurrence (5–7). However, as incidents of RCC continue to increase, representing 2–3% of all adult malignancies, PRCC still receives attention as the second most common subtype of RCC (8–10). Although many genes have been demonstrated to be involved in the development of PRCC in recent years (11), the underlying molecular mechanism of PRCC still remains uncertain. Regarding the PRCC treatment, several agents, such as mechanistic target of rapamycin suppressor and anti-vascular endothelial growth factor agents, are suitable options for patients with progressive and metastatic PRCC, following the support of clinical trials consisting of all RCC subtypes (12). However, specific evidence from patients affected by PRCC is insufficient and controversial, and results from the limited amount of small samples (12). Therefore, it is necessary to investigate the underlying mechanisms of PRCC and search for additional ignored drugs for its treatment.
Although it is difficult to support expenditure in researching novel oncologic therapeutic drugs, the clinical application of a newly-discovered drug typically requires long-term trials to ensure its safety and tolerance in the human body (13). Therefore, the repurposing of known drugs is a feasible drug development strategy, which provides substantial advantages in meeting the high demands of better therapeutic agents in anti-PRCC treatment by searching for more suppressors with known safety but ignored oncologic chemotherapy.
In the present study, the genes that are expressed differently in cases of patients with PRCC and non-PRCC controls were screened using The Cancer Genome Atlas (TCGA) data. A bioinformatics analysis, including Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes (KEGG) enrichment pathway, was performed to explore the underlying mechanism in PRCC. Next, the Connectivity map (Cmap), which is a database that contains >6,900 expression profiles and 1,309 compounds, was used to search for potential drugs for PRCC treatment based on differently expressed genes (DEGs). Then, the hub genes of DEGs in PRCC were selected following the construction of protein-protein interaction (PPI) network analysis, and molecular docking tests between query drugs and hub genes were further performed to validate the prospective application in PRCC treatment.
Materials and methods
Identification of differently expressed genes based on TCGA data
The TCGA database, which comprises 33 cancer types and >10,000 samples, has been widely used to investigate the underlying mechanism in human cancers. GEPIA (14), which is an online tool based on the TCGA data, can be used for DEGs, correlation, survival, and co-expressed genes analyses in various types of cancer. In the present study, GEPIA was used to analyze the DEGs between PRCC tissues and non-PRCC adjacent tissues with one-way analysis of variance (ANOVA) method and Tukey's test, and genes with a q-value <0.05 and ǀlog2fold-change (FC) ǀ>2 were secerned and considered as the significant DEGs.
Functional annotation and KEGG pathway enrichment analysis
For the investigation of the underlying mechanism of PRCC, gene functional annotation and KEGG pathways analyses were performed to explore how aforementioned DEGs function in the onset and development of PRCC (15–17). MetaScape (18) (http://metascape.org), which was updated in 2018, is a web-based tool that provides gene functional annotation and enrichment analysis. In the present study, GO analysis was performed for the gene function annotation by MetaScape, and another tool, Webgestalt (ORA method) (19) (http://www.webgestalt.org), was applied for KEGG pathway enrichment analysis to illustrate which pathways may contribute to the occurrence of PRCC.
Prediction of potential drugs for PRCC treatment based on DEGs by Cmap and Drug Pair Seeker
The Cmap database (20,21) uses gene-expression signatures to predict small molecular compounds for a specific disease. In the present study, the DEGs of PRCC were divided into 2 groups: Upregulated and downregulated genes. Upregulated and downregulated genes were subsequently uploaded to the Cmap in the ‘query’ page, and searches for small molecule drugs that may treat PRCC were performed. Scores ranging from −1-1 represented the correlation between the drug and DEGs. The more negatively correlated drugs indicate greater correlation with the uploaded DEGs and are more likely to be used for PRCC treatment. In the present study, drugs with a score of ≤0.75 were considered as candidate drugs for PRCC treatment. Additionally, Drug Pair Seeker (DPS, version 1.4.0, http://www.maayanlab.net/DPS/) was also utilized to predict which drug from Old AFFY Cmap data could be correlated with the query drug together to reverse the direction of gene expression (22).
Construction of the drug-pathway network
For the exploration of the associations between candidate agents and pathways, the expression profiles for each of the candidate agents were downloaded and the genes affected by candidate drugs were obtained from the Cmap database. The Cmap incorporates 6,100 instances for 1,309 small molecular agents, and each instance includes gene expression profiles of control and corresponding treatment for a certain agent. For each instance, expression profiles of treatment and control were matched for the previously listed candidate drugs according to descriptions of the annotation file. Then, DEGs were identified between control and treatment with log2FC >1 or ≤1 (ORA method) for each candidate drug, and these DEGs were considered as genes that were affected by certain drugs. Finally, these affected genes for each above candidate molecules were entered into SubpathwayMiner (3,23) (an R package for identifying subpathways depend on the KEGG database) to identify significantly enriched subpathways, and a subpathway with false discovery rate (FDR) <0.1 was considered as statistically significant.
Construction of drug-target networks
To further explore the potential mechanism of the top 10 prospective drugs, the SMILE structure of these drugs was obtained from the DrugBank database (https://www.drugbank.ca/). Next, the STITCH database (24) was applied to identify targets of these drugs, and then drug-target networks were construed to show the interactions between the top 10 drugs and their corresponding targets.
Further exploration of query drugs for PRCC treatment
Many types of dysregulated genes are involved in tumorigenesis. To elucidate which genes may serve as key roles in such a complex connection network, a PPI network was constructed for the DEGs of PRCC using the STRING database (25), followed by the identification of the hub genes by CentiScape (26), a plugin of Cytoscape, which may have a key role in the gene regulation network. Next, the expression levels of hub genes were determined by TCGA data in GEPIA. Finally, immunohistochemical (IHC) results of complement C3 (C3) and annexin 1 (ANXA1) in various types of cancers were acquired from the Human Protein Atlas (27) (version 18, https://www.proteinatlas.org/; ANXA1, https://www.proteinatlas.org/ENSG00000135046-ANXA1/pathology; C3, http://wwwhttps://www.proteinatlas.org/ENSG00000125730-C3/pathology), from which the prognostic value of C3 and ANXA1 based on TCGA data (ANXA1, https://www.proteinatlas.org/ENSG00000135046-ANXA1/pathology/tissue/renal+cancer/KIRP; C3, http://www.proteinatlas.org/ENSG00000125730-C3/pathology/tissue/renal+cancer/KIRP), as well as IHC images in renal cancer and normal kidney were also obtained (C3 protein in normal kidney, https://www.proteinatlas.org/ENSG00000125730-C3/tissue/kidney#; C3 protein in renal cancer, https://www.proteinatlas.org/ENSG00000125730-C3/pathology/tissue/renal+cancer#; ANXA1 protein in normal kidney, https://www.proteinatlas.org/ENSG00000135046-ANXA1/tissue/kidney#; ANXA1 protein in renal cancer, http://www.proteinatlas.org/ENSG00000135046-ANXA1/pathology/tissue/renal+cancer#).
To further investigate the potential application of query drugs in PRCC treatment, molecular docking study, as determined by systemsDock (28), a web-online tool for network pharmacology-based prediction and analyses, was performed to simulate the drug-protein interactions between the query drugs and hub genes. This tool provides a high-precision docking simulation and docking pattern map to systematically illustrate the ligand selectivity and the interaction ability between a ligand and proteins, as well as to elucidate how a specific ligand acts on a complex protein. The interaction ability between the query drug and proteins are assessed by docking scores. A drug that interacts well with ANXA1 (PDB code: 1HM6) and C3 (PDB code: 1GHQ; docking score >4) may have a better anticancer application prospect in PRCC as it suppresses the gene regulation network by inhibiting hub genes. A flow chart detailing the experimental design of the present study is presented in Fig. S1.
Statistical analysis
To analyze the genes that are differently expressed in PRCC and non-PRCC adjacent tissues, the one-way ANOVA method and Tukey's test was applied and genes with a q-value <0.05 and ǀlog2FCǀ >2 were selected as the significant DEGs. For GO and KEGG pathway analysis, the overrepresentation enrichment analysis method was used, in which a GO term or pathway with P<0.05 was significant. Following the determination of hub genes among the above DEGs, Kaplan-Meier survival curves were performed to explore their prognostic value in patients with PRCC. Furthermore, the one-way ANOVA method and Tukey's test was also utilized to identify the genes affected by each candidate drug (log2FC >1 or ≤1). Thereafter, these affected genes were used to explore significantly enriched subpathways (FDR<0.1) affected by candidate agents with SubpathwayMiner tool.
Results
GO analysis and KEGG pathway enrichment analysis using DEGs of PRCC
Altogether, 627 DEGs were identified from TCGA data, including 161 upregulated and 466 downregulated genes (Fig. S2). The GO analysis includes three categories (biological process, molecular function, and cellular component), and the 10 significant enrichment terms were displayed for each category (Table I). From the biological process (Fig. 1A), it was observed that DEGs were predominantly associated with anion transport, ion hemostasis and kidney development. For the cellular component (Fig. 1B), these DEGs were enriched in the apical part of the cell, extracellular matrix and basolateral plasma membrane. In molecular function (Fig. 1C), these DEGs were associated with glycosaminoglycan binding, anion transmembrane transporter activity, and calcium ion binding. Regarding the KEGG pathway (Fig. 2; Table II), the results demonstrated that DEGs are significantly associated with complement and coagulation cascades, cell adhesion molecules and mineral absorption.
The drugs of repurposing for PRCC treatment
From the prediction of the Cmap dataset, 60 candidate drugs (after removing duplicates) that scored ≤-0.75 were considered as potential drugs for PRCC treatment (Table SI). The information of the 10 drugs with significant scores is listed in Table III and their 2D molecular structures, as provided by Drugbank (https://www.drugbank.ca/), are displayed in Fig. S3.
 | Table III.Information of the 10 prospective drugs with significant scores for papillary renal cell carcinoma treatment. |
Construction of drug-pathway and drug-target network for candidate drugs
In total, 8 small molecular components among 60 candidate drugs are significantly associated with 9 metabolic pathways (Table SII and Fig. 3). For the 10 significant drugs, the corresponding pathways of vorinostat are p53 and MAPK signing pathway, and the p53 signaling pathway is affected by chlorprothixene. Then, the targets were predicted for the top 10 drugs using the STITCH database; however the targets of pinacidil, ciclosporin, and metacycline were not available. Therefore, only 7 drug-target networks are presented (Fig. 4).
Molecular docking study and drug pairing prediction for vorinostat
Regarding hub genes in the regulation network of DEGs, 9 genes (BDKRB2, C3, PLG, EGF, IGF2, KNG1, CASR, ANXA1 and ADCY4) were selected as hub genes due to their centrality degree ≥15 (Fig. 5). Among these 9 hub genes, 7 genes are significantly downregulated and 2 genes (C3 and ANXA1) are significantly upregulated (Fig. 6), which suggests that C3 and ANXA1 may serve as potential therapeutic targets in the chemotherapy of PRCC. The prognostic value of C3 and ANXA1, as determined by TCGA data, is presented in Fig. 7. Furthermore, the validation of protein levels for C3 and ANXA1 in various types of tumors is presented in Figs. 8 and 9. Distinctly positive C3 protein was observed in tumors' stromal and the majority of malignant cells displayed weak-to-moderate cytoplasmic immunoreactivity. Similarly, most malignant cells displayed moderate-to-strong cytoplasmic and nuclear positivity of ANXA1 protein except breast cancers and malignant lymphomas. Regarding renal cancer tissues, 7 of 13 (53.8%) renal cancer tissues exhibited high/medium C3 protein expression and 9 of 12 (75%) renal cancer tissues exhibited high/medium ANXA1 protein expression. Nevertheless, the expression difference of C3 and ANXN1 protein in renal cancer and non-cancer kidney is not well demonstrated due to the limited controls. Among the top 10 agents, vorinostat was reported to be closely correlated with cell cycle and had been repurposing for the patients with progressive cutaneous T-cell lymphoma (29–32). Consequently, the potential chemotherapy effect of vorinostat in PRCC patients seems to be a feasible investigation. Notably, the molecular docking tests indicate that vorinostat can interact well with ANXA1 and C3 proteins, and that the docking scores for ANXA1 (PDB code: 1HM6; Fig. 10A-C) and C3 (PDB code: 1GHQ; Fig. 10D-F) are 4.866 and 4.634, respectively. Furthermore, the docking results suggest that vorinostat is a potentially prospective agent to treat and reverse PRCC by interfering with gene regulation network through targeting C3 and ANXN1. In addition, the DPS program computationally-predicted which drugs would improve the reversal effects of gene expression changes when combined with vorinostat in PRCC treatment. Via this method, a total of 10 drugs (including propofol and sulfamonomethoxine) were revealed to have latent synergistic effects when combined with vorinostat (Table IV).
| Table IV.Computationally-predicted drugs that may improve the reversal effects of gene expression changes when combined with vorinostat in Drug Pair Seeker. |
Discussion
In the present study, the DEGs of PRCC were identified using TCGA data and a bioinformatics analysis including GO analysis and KEGG pathway was performed to investigate the underlying mechanisms of PRCC. The identified DEGs were also used to search for potential drugs using the Cmap dataset for the treatment of PRCC. Subsequently, the potential application of query drugs in PRCC was further explored with the drug pathway network, drug-target network and a molecular docking test.
According to the GEPIA tool, 627 genes in total were considered as DEGs in PRCC, among which 161 were upregulated genes and 466 were downregulated genes. The GO functional annotation was performed based on these 627 DEGs by MetaScape and it demonstrated that these DEGs were mainly associated with anion transport, ion homeostasis, kidney development, and anion transmembrane transporter activity, which is consistent with other findings that suggest that ion transport has an essential role in tumor development and metastasis by altering substantially normal biological processes (33). The results from the KEGG enrichment pathway, as determined by WebGestalt, also reveal how these DEGS function in PRCC. Among the top 20 metabolic pathways, several significant pathways, such as complement and coagulation cascades and cell adhesion molecules (CAMs), are associated with human tumors (34,35). Cancer migration originates from the disruption of cell adhesion interaction between cancer and normal cells/matrix, followed by an increased cell adhesion activity that interacts with other tissue. Therefore, CAMs is deemed to be a crucial pathway in the development and metastasis of human cancers (36–39). As previously reported, CAMs greatly contributes to migration and invasion in lung cancer, gastric cancer, and bladder cancer (40–42). In a previous study by Zimpfer et al (43), the overexpression of CAMs was located in 126 of 155 patients with PRCC and is clearly associated with higher grade and worse prognosis in PRCC patients. However, the majority of previous studies focused on the investigation of CCRCC, and to date there have been no published studies that investigate how CAMs pathway functions in PRCC based on the molecular mechanism. Therefore, more experiments are required to determine the importance of CAMs in PRCC, which may serve as an ignored therapeutic target in PRCC chemotherapy (44).
To identify more potential drugs for PRCC treatment, 60 candidate drugs were obtained from the prediction of the Cmap dataset depending on DEGs of PRCC. Among the top 10 drugs, vorinostat was particularly interesting and it is considered to be the most promising drug in PRCC treatment for detailed discussion.
Vorinostat, a histone deacetylase (HDAC) suppressor, has been widely applied for therapy in progressive cutaneous T-cell lymphoma via blocking cell cycle and/or inducing cell apoptosis that results from the accumulation of acetylated histone (29–32). In biology, DNA is wrapped around histones and its expression relies on the regulation of acetyltransferases and deacetylases (45). HDACs are a group of enzymes in eukaryotic nuclei that help histone deacetylation, and accordingly allow histones to assemble and transform DNA into bioactive units (46). It was reported that HDACs (HDAC1 and HDAC2) are required for cell growth and survival in RCC tumors (47). The inhibition of HDACs may reverse resistance to angiogenesis inhibitors and enhance oncologic chemotherapy responses in advanced RCC (48). A growing volume of evidence has suggested the incorporation of HDACs in the development of renal tumors, illustrating its decrease or suppression as a prospective therapeutic method to restrain renal tumors (49,50). Recent studies suggest that vorinostat possesses antitumor activity against soft tissue sarcomas, gastric and lung cancer, and even RCC (51–54). In addition, the anti-virus effect of vorinostat in patients with HIV is also reported (55–57). For the safety of vorinostat in clinical application, a clinical trial published in 2017 suggested that the combination of bevacizumab and vorinostat is relatively safe and tolerated in patients with CCRCC (58). Chemotherapy effects of vorinostat for patients with PRCC, however, are still not confirmed by clinical trials. Regarding other drugs, such as naftifine, amiodarone and valproic acid, the antitumor effect of these drugs in human cancers has also been reported in recent years (59–66).
In the present study, the results of drug prediction in Cmap suggest that vorinostat had a relatively low connectivity score, which indicates a high inverse correlation between vorinostat and DEGs of PRCC. From the prediction of drug targets, it was observed that vorinostat is directly targeted to TP53, and there have been a number of published studies, that argue that the mutation of TP53 greatly contributes to the tumorigenesis and development of RCC (67–69). The current study also observed that vorinostat exerts a significant influence in regulating the p53 and MAPK signaling pathway. Previous studies have indicated that both p53 and MAPK signaling pathway are clearly associated with various cellular functions, including apoptosis, cell growth, migration and induction of aging, and serve as key pathways for tumorigenesis and progression in kidney cancers (68,70–74). Therefore, vorinostat may possess an antitumor activity by inhibiting p53 and MAPK signaling pathway.
For a better investigation of the specific molecular mechanism and potential application of vorinostat in anti-PRCC activity, a PPI network was constructed to search for hub genes in the gene regulation network of PRCC. From the PPI network, 9 genes are considered to be hub genes in the DEGs of PRCC, in which 2 genes, C3 and ANXN1, are significantly upregulated. Notably, there was no statistical difference in survival curves for C3 and ANXN1 to support their role in the prognosis of PRCC patients. However, these 2 genes are considered as oncologic therapeutic targets in the PRCC treatment as their key roles of hub genes in the regulation network of DEGs, therefore, the suppression of these 2 genes may interfere with a series of interactions between the DEGs, thereby inhibiting the development and progression of PRCC and then help to treat patients with PRCC. A target drug performs its effects on cancer cells via interaction with the specific proteins encoded by oncogenic or key genes, therefore, molecular docking tests were performed to investigate the drug-protein interactions between vorinostat and these two proteins (C3 and ANXN1). The results provided by systemDock precisely simulate their interaction patterns and illustrate how vorinostat acts on C3 and ANXN1 proteins in the human body. Usually, the binding ability of small molecules and proteins are evaluated by docking scores. Surprisingly, the results as observed from docking tests demonstrate that vorinostat can recognize and interact with both C3 and ANXN1 proteins (docking tests >4), which suggests that vorinostat has a considerably prospective performance in PRCC treatment by suppressing the regulation network of DEGs through inhibiting C3 and ANXN1 proteins. In the future, more experimental evidence and long-term clinical trials are required to validate the effects of vorinostat in PRCC treatment.
Some limitations in the present study remain to be answered. First, the hub genes verified from the PPI network should be further validated in vitro to observe their specific role in PRCC. Second, the effect of potential drugs from Cmap prediction for PRCC treatment should also be further investigated using experimental evidence.
In summary, disregarding the above limitations, 627 DEGs have been identified in PRCC based on TCGA data in the current study, and the underlying mechanism of PRCC has been further investigated by GO and KEGG pathway analysis. Furthermore, to the best of our knowledge, the present study was the first to predict 60 candidate drugs for PRCC treatment based on DEGs by integrating Cmap dataset, in which vorinostat was considered to be the most prospective drug and exhibited significant anti-PRCC activity by inhibiting the regulation network of DEGs by targeting C3 and ANXA1.
Supplementary Material
Supporting Data
Acknowledgements
Not applicable.
Funding
The present study was supported by the Fund of Promoting Project of Basic Capacity for Young and Middle-aged University Teachers in Guangxi (grant no. KY2016LX034) and the Medical Excellence Award Funded by the Creative Research Development Grant from the First Affiliated Hospital of Guangxi Medical University.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
GC, HBY, and SHL involved in the conception and design of the study, as well as designed the figures and tables. JSP, PL, XDW, and ZKL contributed to the statistical analysis, as well as wrote and corrected the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
PRCC |
papillary renal cell carcinoma |
|
TCGA |
The Cancer Genome Atlas |
|
DEGs |
differently expressed genes |
|
GO |
Gene Ontology |
|
KEGG |
Kyoto Encyclopedia of Genes and Genomes |
|
Cmap |
Connectivity Map |
|
CCRCC |
clear renal cell carcinoma |
|
CAMs |
cell adhesion molecules |
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