Integrative analysis of proteomic and transcriptomic data for identification of pathways related to simvastatin‐induced hepatotoxicity

Cho, Young-Eun; Moon, Pyong-Gon; Lee, Jeong Eun; Singh, Thoudam S.K.; Kang, Wonku; Lee, Myung-Hoon; Kim, Sang-Hyun; Baek, Moon‐Chang

doi:10.1002/pmic.201200368

Cited by 33 publications

(30 citation statements)

References 70 publications

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“…A similar correlation coefficient value has been observed by many previous comparative transcriptomics and proteomics studies independent of the proteomics approach (labeling or label-free) and quantification method (spectral count or intensity-based). 62,63 Therefore, the divergence between mRNA and protein is more likely to be driven by post-transcriptional regulation rather than an artifact introduced by the protein quantification method. A simple comparison between differentially expressed mRNAs and proteins (|log2FC| > 1 and adjusted p -value <0.05) identified only 26 common upregulated genes and 19 downregulated genes (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

Integrative Omics Analysis Reveals Post-Transcriptionally Enhanced Protective Host Response in Colorectal Cancers with Microsatellite Instability

Liu

Zhang

2015

J. Proteome Res.

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Microsatellite instability (MSI) is a frequent and clinically relevant molecular phenotype in colorectal cancer. MSI cancers have favorable survival compared with microsatellite stable cancers (MSS), possibly due to the pronounced tumor-infiltrating lymphocytes observed in MSI cancers. Consistent with the strong immune response that MSI cancers trigger in the host, previous transcriptome expression studies have identified mRNA signatures characteristic of immune response in MSI cancers. However, proteomics features of MSI cancers and the extent to which the mRNA signatures are reflected at the protein level remain largely unknown. Here, we performed a comprehensive comparison of global proteomics profiles between MSI and MSS colorectal cancers in The Cancer Genome Atlas (TCGA) cohort. We found that protein signatures of MSI are also associated with increased immunogenicity. To reliably quantify post-transcription regulation in MSI cancers, we developed a resampling-based regression method by integrative modeling of transcriptomics and proteomics data sets. Compared with the popular simple method, which detects post-transcriptional regulation by either identifying genes differentially expressed at the mRNA level but not at the protein level or vice versa, our method provided a quantitative, more sensitive, and accurate way to identify genes subject to differential post-transcriptional regulation. With this method, we demonstrated that post-transcriptional regulation, coordinating protein expression with key players, initiates de novo and enhances protective host response in MSI cancers.

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Section: Resultsmentioning

confidence: 99%

Integrative Omics Analysis Reveals Post-Transcriptionally Enhanced Protective Host Response in Colorectal Cancers with Microsatellite Instability

Liu

Zhang

2015

J. Proteome Res.

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“…Using the 1D-RP-LC method, analysis of 1 g of peptides was performed using the nanoAcquity system (Waters), equipped with a Symmetry C18 5 m, 5 mm × 300 m precolumn and a BEH C18 1.7 m, 25 cm × 75 m analytical RP column (Waters) [14,15,19,20].…”

Section: Lc-esi-ms/ms Analysis (1d-rp-lc and 2d-rp-rp-lc Methods)mentioning

confidence: 99%

An integrated proteomic and transcriptomic approach to understanding azathioprine‐ induced hepatotoxicity in rat primary hepatocytes

2014

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Azathioprine, an immunosuppressant, has gained a prominent position in the clinic for prevention of graft rejection in organ transplants, as well as dermatological autoimmune diseases. However, according to a number of research reports, hepatotoxicity, as one of the side effects, is a major obstacle in azathioprine therapy. In this study, an integrated toxicoproteomic and toxicotranscriptomic analysis was performed using rat primary hepatocytes, in order to gain insight into the in-depth pathway map related to azathioprine-induced hepatotoxicity. For proteomic and transcriptomic analysis, rat primary hepatocytes were exposed to azathioprine at IC20 concentration for 24 h. In particular, 2D LC-MS/MS and informatics-assisted label-free strategy for proteomic analysis were applied in order to increase the number of identified proteins and to improve the confidence of the quantitation results. Among 119 differentially identified protein species, 69 were upregulated and 50 were downregulated in the azathioprine-treated group. At the mRNA level, results of transcriptomic analysis showed increased transcription of 340 genes and decreased transcription of 63 genes in the azathioprine-treated group. Based on the analysis of transcriptomic and proteomic results using the DAVID program, drug metabolism/oxidative stress enzymes, xenobiotic metabolism by cytochrome P450, fatty acid metabolism, primary bile acid biosynthesis, contraction, inflammation metabolism, and mitogen-activated protein kinase (MAPK) kinase (ERK/JNK/p38 kinase) pathways were affected in azathioprine-treated hepatotoxicity. The effects on genes and proteins related to several important pathways were confirmed by real-time PCR and immunoblot analysis, respectively. This study is the first to report on relevant pathways related to azathioprine-induced hepatotoxicity through performance of integrated transcriptomic and proteomic analyses.

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“…Recent evidence indicates that at least some statins activate NRF2. In a proteomic study conducted in isolated hepatocytes, high concentrations of simvastatin activated NRF2, probably as a defensive mechanism (Cho et al, 2013). The pretreatment of neural stem cells with lovastatin activated the NRF2 pathway and elicited protection against hydrogen peroxide-induced cell death (Abdanipour et al, 2014).…”

Section: E Repurposing Instead Of De Novo Drug Discovery and Developmentioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

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Integrative analysis of proteomic and transcriptomic data for identification of pathways related to simvastatin‐induced hepatotoxicity

Cited by 33 publications

References 70 publications

Integrative Omics Analysis Reveals Post-Transcriptionally Enhanced Protective Host Response in Colorectal Cancers with Microsatellite Instability

Integrative Omics Analysis Reveals Post-Transcriptionally Enhanced Protective Host Response in Colorectal Cancers with Microsatellite Instability

An integrated proteomic and transcriptomic approach to understanding azathioprine‐ induced hepatotoxicity in rat primary hepatocytes

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

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