Downregulation of fatty acid oxidation by involvement of HIF-1α and PPARγ in human gastric adenocarcinoma and related clinical significance

Integrating transcriptional profiles results in identifying gene expression signatures that are more robust than those obtained for individual datasets. However, a direct comparison of datasets derived from heterogeneous experimental conditions is problematic, hence their integration requires applying of specific meta-analysis techniques. The transcriptional response to hypoxia has been the focus of intense research due to its central role in tissue homeostasis and prevalent diseases. Accordingly, many studies have determined the gene expression profile of hypoxic cells. Yet, despite this wealth of information, little effort has been made to integrate these datasets to produce a robust hypoxic signature. We applied a formal meta-analysis procedure to datasets comprising 430 RNA-seq samples from 43 individual studies including 34 different cell types, to derive a pooled estimate of the effect of hypoxia on gene expression in human cell lines grown ingin vitro. This approach revealed that a large proportion of the transcriptome is significantly regulated by hypoxia (8556 out of 20,888 genes identified across studies). However, only a small fraction of the differentially expressed genes (1265 genes, 15%) show an effect size that, according to comparisons to gene pathways known to be regulated by hypoxia, is likely to be biologically relevant. By focusing on genes ubiquitously expressed, we identified a signature of 291 genes robustly and consistently regulated by hypoxia. Overall, we have developed a robust gene signature that characterizes the transcriptomic response of human cell lines exposed to hypoxia in vitro by applying a formal meta-analysis to gene expression profiles.

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Section: Discussionmentioning

confidence: 79%

Formal Meta-Analysis of Hypoxic Gene Expression Profiles Reveals a Universal Gene Signature

et al. 2022

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“…On the other hand, the Hallmark signature includes some genes that are induced only in specific cell types or experimental conditions (Figure 6D) and thus, cannot be considered general hypoxia responsive genes. This result is particularly interesting as it explains the contradictory reports regarding the effect of hypoxia on specific genes such as HMOX1 [24][25][26][27][28] and PPARG1 [29][30][31][32][33][34][35] Thus, these results suggest that meta-analysis derived gene signatures are superior to other consolidated methods to identify the genes characteristic of biological processes. Given the widely use of MSigDB genesets in functional enrichment analysis, this conclusion could have far reaching implications.…”

Section: Discussionmentioning

confidence: 85%

Formal meta-analysis of hypoxic gene expression profiles reveals a universal gene signature and cell type-specific effects

Puente-Santamaría

Sanchez-Gonzalez

Gonzalez-Serrano

et al. 2021

Preprint

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BackgroundIntegrating transcriptional profiles results in the identification of gene expression signatures that are more robust than those obtained for individual datasets. However, direct comparison of datasets derived from heterogeneous experimental conditions is not possible and their integration requires the application of specific meta-analysis techniques. The transcriptional response to hypoxia has been the focus of intense research due to its central role in tissue homeostasis and in prevalent diseases. Accordingly, a large number of studies have determined the gene expression profile of hypoxic cells. Yet, in spite of this wealth of information, little effort have been done to integrate these dataset to produce a robust hypoxic signature.ResultsWe applied a formal meta-analysis procedure to a dataset comprising 425 RNAseq samples derived from 42 individual studies including 33 different cell types, to derive a pooled estimate of the effect of hypoxia on gene expression. This approach revealed that a large proportion of the transcriptome (8556 genes out of 20888) is significantly regulated by hypoxia. However, only a small fraction of the differentially expressed genes (1265 genes, 15%) show an effect size that, according to comparisons to gene pathways known to be regulated by hypoxia, is likely to be biologically relevant. By focusing on genes ubiquitously expressed we identified a signature of 291 genes robustly and consistently regulated by hypoxia. Finally, by a applying a moderator analysis we found that endothelial cells show a characteristic gene expression pattern that is significantly different from other cell types.ConclusionBy the application of a formal meta-analysis to hypoxic gene profiles, we have developed a robust gene signature that characterizes the transcriptomic response to low oxygen. In addition to identifying a universal set of hypoxia-responsive genes, we found a set of genes whose regulation is cell-type specific and suggest a unique metabolic response of endothelial cells to reduced oxygen tension.

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“…at the same time, fatty acid metabolism also can be influenced by HIF-1 and HIF-2 (79). Fatty acid oxidation can be affected by HiF-1a; the high expression of HiF-1a and the low expression of the fatty acid oxidative gene is association with reduced PParγ-mediated fatty acid oxidation (80). The gene of HadH is an essential gene of fatty acid oxidation, which seems to be a survival strategy for tumor cells in an anoxic environment (80).…”

Section: Discussionmentioning

confidence: 99%

“…Fatty acid oxidation can be affected by HiF-1a; the high expression of HiF-1a and the low expression of the fatty acid oxidative gene is association with reduced PParγ-mediated fatty acid oxidation (80). The gene of HadH is an essential gene of fatty acid oxidation, which seems to be a survival strategy for tumor cells in an anoxic environment (80). it is hypothesized that the interaction between the gene of HadH and HiF might be the potential mechanism regulating fatty acid oxidation.…”

Section: Discussionmentioning

confidence: 99%

Abnormal expression of HADH, an enzyme of fatty acid oxidation, affects tumor development and prognosis (Review)

et al. 2022

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Tumor occurrence and progression are closely associated with abnormal energy metabolism and energy metabolism associated with glucose, proteins and lipids. The reprogramming of energy metabolism is one of the hallmarks of cancer. as a form of energy metabolism, fatty acid metabolism includes fatty acid uptake, de novo synthesis and β-oxidation. in recent years, the role of abnormal fatty acid β-oxidation in tumors has gradually been recognized. Mitochondrial trifunctional protein (MTP) serves an important role in fatty acid β-oxidation and HadH (two subtypes: α subunit, HadHa and β subunit, HadHB) are important subunits of MTP. HadH participates in the steps of 2, 3 and 4 fatty acid β-oxidation. However, there is no review summarizing the specific role of HADH in tumors. Therefore, the present study focused on HadH as the main indicator to explore the changes in fatty acid β-oxidation in several types of tumors. The present review summarized the changes in HadH in 11 organs (cerebrum, oral cavity, esophagus, liver, pancreas, stomach, colorectum, lymph, lung, breast, kidney), the effect of up-and downregulation and the relationship of HadH with prognosis. in summary, HadH can be either a suppressor or a promoter depending on where the tumor is located, which is closely associated with prognostic assessment. HadHa and HadHB have similar prognostic roles in known and comparable tumors. Contents 1. introduction 2. The roles of HadH in different organs 3. conclusions

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Downregulation of fatty acid oxidation by involvement of HIF-1α and PPARγ in human gastric adenocarcinoma and related clinical significance

Cited by 21 publications

References 44 publications

Formal Meta-Analysis of Hypoxic Gene Expression Profiles Reveals a Universal Gene Signature

Formal Meta-Analysis of Hypoxic Gene Expression Profiles Reveals a Universal Gene Signature

Formal meta-analysis of hypoxic gene expression profiles reveals a universal gene signature and cell type-specific effects

Abnormal expression of HADH, an enzyme of fatty acid oxidation, affects tumor development and prognosis (Review)

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