Gastric cancer cells exploit FABP5 via the PD-L1/TNF/IL-17 signaling axis
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ABSTRACT: Background: Gastric cancer (GC) is the second most lethal cancer globally and is associated with poor prognosis. Fatty acid-binding proteins (FABPs) can regulate the biological properties of carcinoma cells. FABP5 is overexpressed in many types of cancers; however, the role and mechanism of FABP5 in GC are still unclear. Aim: In this study, we aimed to evaluate the clinical and biological function of FABP5 in GC. Methods: We assessed FABP5 expression using immunohistochemical analysis of 79 GC patients and evaluated its biological functions following in vitro and in vivo ectopic expression. FABP5 targets relevant to GC progression were determined using RNA sequencing (RNA-seq) analyses. Results: Elevated FABP5 expression was closely related to poor outcomes, and ectopic expression of FABP5 promoted GC cell proliferation, invasion, migration, and carcinogenicity, suggesting its potential tumor-promoting role in GC. Additionally, RNA-seq analysis indicated that FABP5 activates immune-related pathways, including cytokine–cytokine receptor-interaction pathways, interleukin-17 signaling, and tumor necrosis factor signaling, suggesting an important rationale for the possible development of therapies combining FABP5-targeted drugs with immunotherapeutics. Conclusion: These findings highlight the biological mechanisms and clinical implications of FABP5 in GC and suggest its potential as an adverse prognostic factor and/or therapeutic target.
Project description:Regulatory T cells (Tregs) negatively regulate immune-mediated inflammation that is essential for preventing autoimmunity, but which can be detrimental in cancer. Central to Treg activation are changes in lipid metabolism to support their survival and function. Fatty acid binding proteins (FABPs) are a family of lipid chaperones required to facilitate the uptake and trafficking of intracellular lipids. One family member, FABP5, is expressed in certain T cell subsets, but its function remains elusive. We show here that in Tregs, FABP5 inhibition causes mitochondrial defects, underscored by decreased OXPHOS, lipid elongation and desaturation, and loss of cristae structure, which augment their suppressive function. Mitochondrial dysfunction after FABP5 inhibition results in mtDNA release and consequent cGAS/STING-dependent type I IFN signaling, which induces increased production of the regulatory cytokine IL-10, promoting Treg cell suppressive activity. Together these data reveal that FABP5 acts as a gatekeeper of mitochondrial health to control Treg cell function.
Project description:We used RNA-seq to study the function of FABP5 in gastric cancer cells (AGS and MGC803). Down-regulation of FABP5 suppressed cell proliferation, cell migration and invasion, and induced cell apoptosis. Bioinformatics analysis revealed that Hippo signaling pathway was related to FABP5 in GC cells.Our data suggested that FABP5 might act as a potential target associated with Hippo signaling pathway for GC treatment.
Project description:Purpose: Mouse BMDM is the universal cell type of studying innate immunity. This study was designed to analyze LPS induced innate immune response and the gene expression in FABP5 KO BMDMs with overexpression of FABP5 WT or FABP5 C127S. Methods: FABP5 KO BMDMs were nucleofected with 5 μg pXJ40-3xFlag-FABP5 WT or C127S plasmid using the Amaxa Mouse Macrophage Nucleofector Kit (Lonza, VPA-1009) following the manufacturer’s instructions. Replace medium 6 hours post Nucleofection and add 500 ng/mL LPS to the fresh medium. 24 hours after treatment, harvest cells by using GenElute Single Cell RNA Purification Kit (Sigma, RNB300) and perform RNA-seq. Then mRNA profiles of these samples were generated by high-throughput sequencing analysis, using Illumina NovaSeq6000. And the differential mRNA profiles were analyzed. Results: mRNA profiles were analyzed, and differential expression profiles were compared. Conclusions: Our study demonstrated the transcriptional profiles of FABP5 KO BMDMs with overexpression of FABP5 WT or FABP5 C127S upon LPS treatment, with biologic replicates, generated by RNA-seq technology.
Project description:Multiple myeloma (MM) is an incurable plasma cell malignancy that causes anemia, osteolysis, hypercalcemia, and organ failure, with only a 53% 5-years survival rate. Herein, we present data demonstrating a novel target in MM: the fatty acid binding protein (FABP) family. In clinical data, FABP5 represented a novel biomarker for more aggressive cancer. FABP inhibitors decreased tumor burden in vitro and in vivo and increased survival in immunocompetent and immunocompromised mouse models. FABP5 was the most highly expressed FABP member in myeloma cells, and the most essential for their survival. CRISPR-Cas9 generated FABP5-KO MM.1S cells showed inhibited growth potential. RNA-sequencing and metabolic analysis identified new pathways of action for the FABPs, including MYC, the unfolded protein response (UPR), and metabolic changes. Collectively, our results demonstrate that FABPs comprise a novel, targetable, and safe, therapeutic avenue for MM and other cancers, and suggest inhibiting FABPs may be worthy of further study.
Project description:Differential susceptibility to recurrent infection and exacerbation in COPD is not well understood. Here we investigated the potential impact of genetic variation in Fatty Acid Binding Protein 5 (FABP5), a metabolic regulator we previously demonstrated to be downregulated in COPD and further downregulated in patients reporting one or more exacerbation. Through negative binomial analysis of the COPDGene SNP dataset, we identified 5 novel linked single nucleotide polymorphisms (SNPs) across the FABP5 locus that were significantly associated with severe exacerbations in a Non-Hispanic White cohort (rs4338057, rs12549270, rs202275, rs202277, and rs202279). We integrated multiple sources of previously published data to prioritize SNPs most likely to exert regulatory function. Ultimately, rs202275 emerged as the lead candidate due to unique alignment with the loading site of a bidirectional RNA Pol II signature of active enhancer utilization in our recently published patient-derived airway epithelial PRO-seq dataset, suggesting a critical regulatory role for the region harboring this variant. Using Micro-C genome-wide chromosome conformation capture, we found that the region harboring rs202275 makes three-dimensional physical contacts with the FABP5 transcription start site (TSS), suggesting the SNP region could regulate FABP5 transcription through a looping mechanism. To examine SNP function, we analyzed previously deposited gene-array data (GEO Accession #GSE42057) from peripheral blood mononuclear cell (PBMC) samples and found that COPD patients carrying the rs202275 risk allele (T) express significantly lower levels of FABP5 compared to non-carrier patients. Seahorse real-time mitochondrial respiration assays in freshly isolated PBMCs further revealed disrupted oxidative phosphorylation in cells from patients carrying the rs202275 risk allele. As macrophage polarization from pro-inflammatory toward pro-resolving phenotype is dependent on oxidative metabolism, the functional impact of the rs202275 risk allele and associated reduction in FABP5 transcription may contribute to increased or prolonged systemic inflammation, thereby increasing susceptibility to exacerbation in COPD.
Project description:Gene expression profile of treatment with FABP4 or FABP5 in ADSC and 233A cells was examined. ADSC or 233A cells were treated with and without 1 µM recombinant FABP4 or FABP5.
Project description:High-throughput sequencing analysis of mouse FABP5 KO BMDM cell transcriptomes with overexpression of FABP5 WT or FABP5 C127S after LPS treatment
Project description:To investigate the function of FABP5 in the regulation of metabolic reprogramming in Huh7 cells in which target gene has been silenced by siRNA or inhibited by competitive inhibitor SBFI-103.