Multiomics-based analyses of KPNA2 highlight its multiple potentials in hepatocellular carcinoma

Dysregulation and prognostic roles of Karyopherin α2 (KPNA2) were reported in many malignancies including hepatocellular carcinoma (HCC). A multi-omics analysis of KPNA2 is needed to gain a deeper understanding of its multilevel molecular characteristics and provide novel clues for HCC diagnosis, prognosis, and target therapy. Herein multi-omic alterations of KPNA2 were analyzed at genetic, epigenetic, transcript, and protein levels with evaluation of their relevance with clinicopathological features of HCC by integrative analyses. The significant correlations of KPNA2 expression with its gene copy number variation (CNV) and methylation status were shown through Spearman correlation analyses. With Cox regression, Kaplan-Meier survival, and receiver operating characteristic (ROC) analyses, based on the factors of KPNA2 CNV, methylation, expression, and tumor stage, risk models for HCC overall survival (OS) and disease-free survival (DFS) were constructed which could discriminate the 1-year, 3-year, and 5-year OS/DFS status effectively. With Microenvironment Cell Populations-counter (MCP-counter), the immune infiltrations of HCC samples were evaluated and their associations with KPNA2 were shown. KPNA2 expression in liver was found to be influenced by low fat diet and presented significant correlations with fatty acid metabolism and fatty acid synthase activity in HCC. KPNA2 was detected lowered in HCC patient’s plasma by enzyme linked immunosorbent assay (ELISA), consistent with its translocation to nuclei of HCC cells. In conclusion, KPNA2 multilevel dysregulation in HCC and its correlations with immune infiltration and the fatty acid metabolism pathway indicated its multiple roles in HCC. The clinicopathological significance of KPNA2 was highlighted through the in-depth analyses at multilevels.

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Tumor metabolism and associated serum metabolites define prognostic subtypes of Asian hepatocellular carcinoma

Scientific Reports ◽

10.1038/s41598-021-91560-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yotsawat Pomyen ◽

Anuradha Budhu ◽

Jittiporn Chaisaingmongkol ◽

Marshonna Forgues ◽

Hien Dang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Treatment Effectiveness ◽

Data Types ◽

Serum Metabolites ◽

Non Invasive ◽

Metabolic Genes ◽

Tissue Metabolites

AbstractTreatment effectiveness in hepatocellular carcinoma (HCC) depends on early detection and precision-medicine-based patient stratification for targeted therapies. However, the lack of robust biomarkers, particularly a non-invasive diagnostic tool, precludes significant improvement of clinical outcomes for HCC patients. Serum metabolites are one of the best non-invasive means for determining patient prognosis, as they are stable end-products of biochemical processes in human body. In this study, we aimed to identify prognostic serum metabolites in HCC. To determine serum metabolites that were relevant and representative of the tissue status, we performed a two-step correlation analysis to first determine associations between metabolic genes and tissue metabolites, and second, between tissue metabolites and serum metabolites among 49 HCC patients, which were then validated in 408 additional Asian HCC patients with mixed etiologies. We found that certain metabolic genes, tissue metabolites and serum metabolites can independently stratify HCC patients into prognostic subgroups, which are consistent across these different data types and our previous findings. The metabolic subtypes are associated with β-oxidation process in fatty acid metabolism, where patients with worse survival outcome have dysregulated fatty acid metabolism. These serum metabolites may be used as non-invasive biomarkers to define prognostic tumor molecular subtypes for HCC.

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FC 102PD INDUCED ARTERIOLAR AND PERITONEAL PATHOMECHANISMS ARE PARTIALLY REVERSED AFTER KIDNEY TRANSPLANTATION

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab135.001 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Conghui Zhang ◽

Maria Bartosova ◽

Betti Schaefer ◽

Rebecca Herzog ◽

Rimante Cerkauskiene ◽

...

Keyword(s):

Kidney Transplantation ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Fatty Acid Synthase ◽

Molecular Mechanisms ◽

Acid Metabolism ◽

Parietal Peritoneum ◽

Gene Set Enrichment Analysis ◽

Biological Processes ◽

Cell Counts

Abstract Background and Aims Due to the unphysiological composition of PD fluids, chronic peritoneal dialysis (PD) induces progressive peritoneal fibrosis, hypervascularization, and vasculopathy. The evolution of the PD membrane and vasculopathy following kidney transplantation (KTx) is largely unknown. Method Arteriolar and peritoneal tissues were obtained from 107 children with chronic kidney disease (CKD5), 72 children on PD (treated with neutral pH PD fluids, with low glucose degradation product content, GDP) and 21 children, who underwent KTx 4-5 weeks after a median 21 months of PD. Specimen underwent standardized digital quantitative histomorphometry. Molecular mechanisms were studied in omental arterioles microdissected from surrounding fat by multi-omics followed by Gene Set Enrichment Analysis (GSEA); key findings were validated in parietal tissues of independent, matched cohorts by quantitative immunohistochemistry (n=15/group). Results Arteriolar transcriptome and proteome GSEA revealed suppression of leucocyte migration and T-cell activation / secretory pathways regulation, of sprouting angiogenesis biological processes and of epithelial proliferation and cell cycle after KTx as compared to PD. Lipid / fatty acid metabolism, autophagy and ATP synthesis pathways were activated. Transcriptome analysis including KTx, PD and CKD5 specifically attributed regulation of arteriolar lipid and fatty acid metabolism to transplantation and comprised 140 transcripts; their regulation was confirmed on the proteome level. Hub gene fatty acid synthase was identified by protein interaction analysis (string-db.org). 15 arteriolar genes activated by PD were inactivated after KTx and included glucose metabolisms and cytoskeleton related transcripts. 24 transcripts and 10 corresponding proteins induced by PD were still active after KTx and associated with biological processes related to TGF-ß signaling, fibrosis and mineral absorption. In line with arteriolar multi-omics findings, peritoneal hypervascularization induced by chronic PD was reversed after Tx to CKD5 level. CD45 positive tissue infiltrating leucocytes count was reduced by 40% and was independently associated with microvessel density in multivariable analysis including PD vintage, daily GDP exposure and recent KTx. Peritoneal lymphatic vessel density, submesothelial thickness, activated fibroblast, fibrin deposit, macrophage and EMT cell counts remained unchanged after KTx compared to PD. Arteriolar lumen to vessel ratios (a marker of vasculopathy) were similar in both groups. Vessel-homeostasis-related proteins in independent, matched cohorts demonstrated increased caspase-3 abundance in peritoneal arterioles after KTx. Arteriolar VEGF-A, thrombospondin, angiopoietin1/2, and hypoxia-inducible factor-1 (HIF-1a) were unchanged, while submesothelial HIF-1a and angiopoietin1/2 were decreased after Tx, favoring vessel maturation. The abundance of the key driver of fibrosis, TGF-ß-effector pSMAD2/3, was unchanged in the peritoneum and arterioles after Tx. Conclusion Our multi-omics analyses of fat covered omental arterioles, not directly exposed to PD fluids, demonstrate inhibition of PD induced immune response and angiogenesis pathways, of glucose metabolism and cytoskeleton regulation to levels similar as seen in children with CKD5. Arteriolar lipid and fatty acid metabolism is selectively altered after KTx. Reversal of low GDP PD induced hypervascularization and inflammation of the parietal peritoneum after KTx, mirror molecular changes in omental arterioles, while profibrotic activity persists after KTx in omental arterioles and in the parietal peritoneum.

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Fatty acid synthase promotes breast cancer metastasis by mediating changes in fatty acid metabolism

Oncology Letters ◽

10.3892/ol.2020.12288 ◽

2020 ◽

Vol 21 (1) ◽

pp. 1-1

Author(s):

Shuo Xu ◽

Tingting Chen ◽

Lihua Dong ◽

Tao Li ◽

Hui Xue ◽

...

Keyword(s):

Breast Cancer ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Fatty Acid Synthase ◽

Cancer Metastasis ◽

Acid Metabolism ◽

Breast Cancer Metastasis

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The effect of fetal pig size and stage of gestation on tissue fatty acid metabolism and profile

Reproduction ◽

10.1530/rep.1.00451 ◽

2005 ◽

Vol 129 (6) ◽

pp. 757-763 ◽

Cited By ~ 9

Author(s):

Christopher J McNeil ◽

Angela M Finch ◽

Kenneth R Page ◽

Steve D Clarke ◽

Cheryl J Ashworth ◽

...

Keyword(s):

Fatty Acid ◽

Fetal Growth ◽

Fatty Acid Metabolism ◽

Fatty Acid Synthase ◽

Porcine Model ◽

Acid Metabolism ◽

Fatty Acid Status ◽

Δ5 Desaturase ◽

Acid Status ◽

Δ6 Desaturase

The fetus requires an adequate supply of fatty acids for optimum growth and development. It has been hypothesized that reduced activity of enzymes of fatty acid metabolism could contribute to inadequate fetal growth. In a porcine model of differential fetal growth we examined heart and liver fatty acid synthase, Δ5-desaturase and Δ6-desaturase gene expression and measured hepatic fatty acid profile to assess long-chain polyunsaturated fatty acid status. On gestation days 45, 65 and 100 sows were killed and tissues extracted from an average-sized fetus and the smallest fetus from each litter. As early as day 45, considerable hepatic Δ5- and Δ6-desaturase was detected, and this expression significantly increased as gestation progressed. In contrast, cardiac desaturase expression remained stable with time. Fatty acid synthase expression was greatest at day 65 in the liver, but was not expressed in the heart. Overall, the smallest fetus did not exhibit reduced tissue Δ5- or Δ6-desaturase expression or compromised polyunsaturated fatty acid status at any stage. In fact, small fetuses expressed more cardiac Δ5-desaturase than their average-sized siblings, possibly in response to a stress to the heart. It is clear from this study that fatty acid metabolism changes markedly as gestation progresses, and reduced fatty acid supply does not cause inadequate growth in this porcine model of fetal development.

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ACSL4 reprograms fatty acid metabolism in hepatocellular carcinoma via c-Myc/SREBP1 pathway

Cancer Letters ◽

10.1016/j.canlet.2020.12.019 ◽

2020 ◽

Author(s):

Junru Chen ◽

Chaofeng Ding ◽

Yunhao Chen ◽

Wendi Hu ◽

Chengkuan Yu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism

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Prognostic value of fatty acid metabolism-related genes in patients with hepatocellular carcinoma

Aging ◽

10.18632/aging.203288 ◽

2021 ◽

Author(s):

Dongsheng He ◽

Lifang Cai ◽

Weiming Huang ◽

Qingqing Weng ◽

Xi Lin ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Prognostic Value ◽

Acid Metabolism

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The transcriptome of early GGT/KRT19-positive hepatocellular carcinoma reveals a downregulated gene expression profile associated with fatty acid metabolism

Genomics ◽

10.1016/j.ygeno.2021.11.035 ◽

2021 ◽

Author(s):

María Paulette Castro-Gil ◽

Julia Esperanza Torres-Mena ◽

Rosa M. Salgado ◽

Said A. Muñoz-Montero ◽

José Michael Martínez-Garcés ◽

...

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

Fatty Acid ◽

Gene Expression Profile ◽

Expression Profile ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Downregulated Gene

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Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

Cancers ◽

10.3390/cancers12092579 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2579

Author(s):

Diana Oelschlaegel ◽

Tommy Weiss Sadan ◽

Seth Salpeter ◽

Sebastian Krug ◽

Galia Blum ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Metabolism ◽

Immune Cells ◽

Fatty Acid Synthase ◽

Acid Metabolism ◽

Metabolic Reprogramming ◽

Marker Genes ◽

Tumor Associated Macrophages ◽

Cathepsin Activity ◽

The Impact

Stroma-infiltrating immune cells, such as tumor-associated macrophages (TAM), play an important role in regulating tumor progression and chemoresistance. These effects are mostly conveyed by secreted mediators, among them several cathepsin proteases. In addition, increasing evidence suggests that stroma-infiltrating immune cells are able to induce profound metabolic changes within the tumor microenvironment. In this study, we aimed to characterize the impact of cathepsins in maintaining the TAM phenotype in more detail. For this purpose, we investigated the molecular effects of pharmacological cathepsin inhibition on the viability and polarization of human primary macrophages as well as its metabolic consequences. Pharmacological inhibition of cathepsins B, L, and S using a novel inhibitor, GB111-NH2, led to changes in cellular recycling processes characterized by an increased expression of autophagy- and lysosome-associated marker genes and reduced adenosine triphosphate (ATP) content. Decreased cathepsin activity in primary macrophages further led to distinct changes in fatty acid metabolites associated with increased expression of key modulators of fatty acid metabolism, such as fatty acid synthase (FASN) and acid ceramidase (ASAH1). The altered fatty acid profile was associated with an increased synthesis of the pro-inflammatory prostaglandin PGE2, which correlated with the upregulation of numerous NFkB-dependent pro-inflammatory mediators, including interleukin-1 (IL-1), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor-alpha (TNFα). Our data indicate a novel link between cathepsin activity and metabolic reprogramming in macrophages, demonstrated by a profound impact on autophagy and fatty acid metabolism, which facilitates a pro-inflammatory micromilieu generally associated with enhanced tumor elimination. These results provide a strong rationale for therapeutic cathepsin inhibition to overcome the tumor-promoting effects of the immune-evasive tumor micromilieu.

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