Abstract
BackgroundAmong all causes of death, cancer is the most prevalent and is only outpaced by cardiovascular diseases. Molecular theory of carcinogenesis states that apoptosis and proliferation are regulated by groups of tumor suppressors or oncogenes. Transcription factors are example of proteins comprising representatives of both cancer-related groups. Exemplary family of transcription factors which exhibits dualism of function is Activating enhancer-binding Protein 2 (AP-2). Scientific reports concerning their function in carcinogenesis depend on particular family member and/or tumor type which proves the issue to be unsolved. Therefore, the present study examines role of the best-described AP-2 representatives, AP-2α and AP-2γ, through ontological analysis of their target genes and investigation what processes are differentially regulated in 21 cancers using samples deposited in Genomic Data Analysis Center (GDAC) Firehose.MethodsExpression data with clinical annotation was collected from TCGA-dedicated repository GDAC Firehose. Transcription factor targets were obtained from Gene Transcription Regulation Database (GTRD), TRANScription FACtor database (TRANSFAC) and Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TRRUST). Monocle3 R package was used for global samples profiling while Protein ANalysis THrough Evolutionary Relationships (PANTHER) tool was used to perform gene ontology analysis.ResultsWith RNA-seq data and Monocle3 or PANTHER tools we outlined differences in many processes and signaling pathways, separating tumor from normal tissues or tumors from each other. Unexpectedly, a number of alterations in basal-like breast cancer were identified that distinguished it from other subtypes, which could bring future clinical benefits.ConclusionsOur findings indicate that while the AP-2α/γ role remains ambiguous, their activity is based on processes that underlie the cancer hallmarks and their expression could have potential in diagnosis of selected tumors.
Highlights
Among all causes of death, cancer is the most prevalent and is only outpaced by cardiovascular diseases
Identification of global differences using toolkit for spatial analysis Considered cohorts were clustered according to designed variable discriminating tumors and their corresponding normal tissues. Their distribution across Uniform Manifold Approximation and Projection (UMAP) dimensions was presented according to the genetic targets for a given transcription factor (AP-2α or AP-2γ)
The analysis based on AP-2α identified a group of cancers distinct from other separated clusters but to a lesser extent from the corresponding normal tissue: Liver hepatocellular carcinoma (LIHC), Kidney renal papillary cell carcinoma (KIRP), Kidney renal clear cell carcinoma (KIRC), Prostate adenocarcinoma (PRAD), Skin cutaneous melanoma (SKCM), Ovarian serous cystadenocarcinoma (OV), Thyroid carcinoma (THCA), Breast invasive carcinoma (BRCA), Stomach adenocarcinoma (STAD), Lung adenocarcinoma (LUAD) and Pancreatic adenocarcinoma (PAAD)
Summary
Among all causes of death, cancer is the most prevalent and is only outpaced by cardiovascular diseases. Exemplary family of transcription factors which exhibits dualism of function is Activating enhancerbinding Protein 2 (AP-2) Scientific reports concerning their function in carcinogenesis depend on particular family member and/or tumor type which proves the issue to be unsolved. The members of the Activating enhancer-binding Protein 2 (AP-2) family demonstrate ambiguity; of these, AP-2α exhibits dualism of function depending on its related signaling pathway [11, 12]. Another AP-2 protein, AP-2γ, was thought to have oncogenic activity since its transcriptional activity is inhibited by WW Domain Containing Oxidoreductase (WWOX) tumor suppressor after its sequestration outside the nucleus [13]. The other reports indicating that AP-2γ induces expression of p21 protein suggest that it may demonstrate anti-tumoral traits [14], presenting contrasting function which prompts consideration
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