A Transcriptomic and Reverse-Engineering Strategy Reveals Molecular Signatures of Arachidonic Acid Metabolism in 12 Cancers.

Cancer and arachidonic acid (AA) have important linkages. For example, AA metabolites regulate several critical biological functions associated with carcinogenesis: angiogenesis, apoptosis, and cancer invasion. However, little is known about the comparative changes in metabolite expression of the arachidonic acid pathway (AAP) in carcinogenesis. In this study, we examined transcriptome data from 12 cancers, such as breast invasive carcinoma, colon adenocarcinoma, lung adenocarcinoma, and prostate adenocarcinoma. We also report here a reverse-engineering strategy wherein we estimated metabolic signatures associated with AAP by (1) making deductive inferences through transcriptome-level data extraction, (2) remodeling AA metabolism, and (3) performing a comparative analysis of cancer types to determine the similarities and differences between different cancer types with respect to AA metabolic alterations. We identified 77 AAP gene signatures differentially expressed in cancers and 37 AAP metabolites associated with them. Importantly, the metabolite 15(S)-HETE was identified in almost all cancers, while arachidonate, 5-HETE, PGF2α, 14,15-EET, 8,9-EET, 5,6-EET, and 20-HETE were discovered as other most regulated metabolites. This study shows that the 12 cancers studied herein, although in different branches of the AAP, have altered expression of AAP gene signatures. Going forward, AA related-cancer research generally, and the molecular signatures and their estimated metabolites reported herein specifically, hold broad promise for precision/personalized medicine in oncology as potential therapeutic and diagnostic targets.

Drug Repositioning Identifies Six Drug Candidates for Systemic Autoimmune Diseases by Integrative Analyses of Transcriptomes from Scleroderma, Systemic Lupus Erythematosus, and Sjogren's Syndrome.

The mechanisms of systemic autoimmune diseases (ADs) are still not clearly understood. Understanding the etiology of systemic ADs and identifying new therapeutic targets require a systems science approach. Using publicly available transcriptome data and bioinformatic analysis, we investigated the differential gene expression profiles of patients with scleroderma, systemic lupus erythematosus, and Sjogren's syndrome. Of these common differentially expressed gene signatures, 208 were regulated in the same direction (either upregulated or downregulated in all datasets) and used for drug repositioning. Six small molecule drug candidates (KU-0063794, YM-155 [sepantronium bromide], MST-312 [telomerase inhibitor IX], PLX-4720, ZM 336372, and 528116.cdx [PIK-75]) were discovered by drug repositioning as potential therapeutics for systemic ADs. The Search Tool for Chemical Interactions was used to find the anticipated target genes of the repositioned molecules. The PI3K/AKT pathway topped the list of common enriched pathways with the most anticipated target genes of the six repositioned small molecules. We also report here the molecular docking findings on the binding affinity between the repositioned drug candidates and genes from the protein-protein interaction network modules of anticipated target genes. Taken together, this study provides new insights and opens up new possibilities on both pathogenesis and treatment of systemic ADs through drug repositioning.

Cancer Drug Repositioning by Comparison of Gene Expression in Humans and Axolotl (Ambystoma mexicanum) During Wound Healing.

Urodele amphibians such as the axolotl (Ambystoma mexicanum) display a large capacity for tissue regeneration and remarkable resistance to cancer. As a model organism, axolotl thus offers a unique opportunity for cancer research and anticancer drug discovery, not to mention the discerning mechanisms that underpin controlled cellular growth and regeneration versus cancer. To the best of our knowledge, little is known on comparative gene expression changes during regeneration events such as wound healing in axolotl and humans. Using publicly available transcriptomics data and bioinformatics analyses, we examined the differential gene expression signatures in skin wound samples from axolotl and humans after skin biopsy punch injury, in comparison with intact (uninjured) control skin samples. We identified 95 genes exhibiting a reversal expression pattern between humans and axolotl during the wound healing/regeneration period. These genes were significantly associated with collagen biosynthesis, extracellular matrix organization, PI3K-Akt signaling pathway, immune system response, and apoptotic process. Furthermore, this new gene set exhibited high prognostic performance in discriminating the survival risk in skin-related cancers, including melanoma (hazard ratio [HR] = 8.14, p < 10-30), oral cancer (HR >100, p < 10-12), and head and neck carcinoma (HR = 5.29, p < 10-30). Moreover, considering these gene signatures, we repositioned 11 small molecules as potential anticancer drug candidates indicating reversal effects on upregulated human genes and downregulated axolotl genes or mimicking downregulated human genes and upregulated axolotl genes. We anticipate that this study offers new insights on gene signatures bridging regeneration mechanisms with tumorigenesis and cancer drug repositioning.