Ancient ubiquitous protein 1 (AUP1) is a prognostic biomarker connected with TP53 mutation and the inflamed microenvironments in glioma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE227721 | GEO | 2023/03/24
REPOSITORIES: GEO
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Project description:IntroductionGlioblastoma (GBM) is the most common and lethal brain tumor. The current treatment is surgical removal combined with radiotherapy and chemotherapy, Temozolomide (TMZ). However, tumors tend to develop TMZ resistance which leads to therapeutic failure. Ancient ubiquitous protein 1 (AUP1) is a protein associated with lipid metabolism, which is widely expressed on the surface of ER and Lipid droplets, involved in the degradation of misfolded proteins through autophagy. It has recently been described as a prognostic marker in renal tumors. Here, we aim to use sophisticated bioinformatics and experimental validation to characterize the AUP1's role in glioma.Material and methodsWe collected the mRNA, proteomics, and Whole-Exon-Sequencing from The Cancer Genome Atlas (TCGA) for bioinformatics analyses. The analyses included the expression difference, Kaplan-Meier-survival, COX-survival, and correlation to the clinical factors (tumor mutation burden, microsatellite instability, and driven mutant genes). Next, we validated the AUP1 protein expression using immunohistochemical staining on the 78 clinical cases and correlated them with P53 and KI67. Then, we applied GSEA analyses to identify the altered signalings and set functional experiments (including Western Blot, qPCR, BrdU, migration, cell-cycle, and RNAseq) on cell lines when supplemented with small interfering RNA targeting the AUP1 gene (siAUP1) for further validation. We integrated the single-cell sequencing and CIBERSORT analyses at the Chinese Glioma Genome Atlas (CGGA) and Glioma Longitudinal AnalySiS (GLASS) dataset to rationale the role of AUP1 in glioma.ResultsFirstly, the AUP1 is a prognostic marker, increased in the tumor component, and correlated with tumor grade in both transcriptomes and protein levels. Secondly, we found higher AUP1 associated with TP53 status, Tumor mutation burden, and increased proliferation. In the function validation, downregulated AUP1 expression merely impacted the U87MG cells' proliferation instead of altering the lipophagy activity. From the single-cell sequencing and CIBERSORT analyses at CGGA and GLASS data, we understood the AUP1 expression was affected by the tumor proliferation, stromal, and inflammation compositions, particularly the myeloid and T cells. In the longitudinal data, the AUP1 significantly dropped in the recurrent IDH wildtype astrocytoma, which might result from increased AUP1-cold components, including oligodendrocytes, endothelial cells, and pericytes.ConclusionAccording to the literature, AUP1 regulates lipophagy by stabilizing the ubiquitination of lipid droplets. However, we found no direct link between AUP1 suppression and altered autophagy activity in the functional validation. Instead, we noticed AUP1 expression associated with tumor proliferation and inflammatory status, contributed by myeloid cells and T cells. In addition, the TP53 mutations seem to play an important role here and initiate inflamed microenvironments. At the same time, EGFR amplification and Chromosome 7 gain combined 10 loss are associated with increased tumor growth related to AUP1 levels. This study taught us that AUP1 is a poorer predictive biomarker associated with tumor proliferation and could report inflamed status, potentially impacting the clinical application.
| S-EPMC10080956 | biostudies-literature
Project description:Ancient ubiquitous protein 1 (AUP1) is a prognostic biomarker connected with TP53 mutation and the inflamed microenvironments in glioma
| PRJNA946715 | ENA
Project description:BackgroundApproximately 15-30% of hospitalized COVID-19 patients develop acute respiratory distress syndrome, systemic tissue injury, and/or multi-organ failure leading to death in around 45% of cases. There is a clear need for biomarkers which quantify tissue injury, predict clinical outcomes and guide the clinical management of hospitalized COVID-19 patients.MethodsWe herein report the quantification by droplet-based digital PCR (ddPCR) of the SARS-CoV-2 RNAemia and the plasmatic release of a ubiquitous human intracellular marker, the ribonuclease P (RNase P) in order to evaluate tissue injury and cell lysis in the plasma of 139 COVID-19 hospitalized patients at admission.ResultsWe confirmed that SARS-CoV-2 RNAemia was associated with clinical severity of COVID-19 patients. In addition, we showed that plasmatic RNase P RNAemia at admission was also highly correlated with disease severity (P<0.001) and invasive mechanical ventilation status (P<0.001) but not with pulmonary severity. Altogether, these results indicate a consequent cell lysis process in severe and critical patients but not systematically due to lung cell death. Finally, the plasmatic RNase P RNA value was also significantly associated with overall survival.ConclusionViral and ubiquitous blood biomarkers monitored by ddPCR could be useful for the clinical monitoring and the management of hospitalized COVID-19 patients. Moreover, these results could pave the way for new and more personalized circulating biomarkers in COVID-19, and more generally in infectious diseases, specific from each patient organ injury profile.
| S-EPMC8689820 | biostudies-literature
Project description:H2A family member Z (H2AFZ) is a highly conserved gene encoding H2A.Z.1, an isoform of histone variant H2A.Z, and is implicated in cancer. In this study, we report that overexpression of H2AFZ is associated with tumor malignancy and poor prognosis in HCC patients. Functional network analysis suggested that H2AFZ mainly regulates cell cycle signaling and DNA replication via pathways involving several cancer-related kinases and transcription factor E2F1. Further studies revealed that H2AFZ overexpression is regulated by TP53 mutation and led to an attenuation of rapid proliferation phenotype and aggressive behavior in HCC cells. Moreover, we found that H2AFZ was related to immune infiltrations and was co-expressed with immune checkpoint genes, including CD274 (PD-L1), CTLA-4, HAVCR2 (TIM3), LAG3, PDCD1 (PD-1), and TIGIT (VSIG9) in HCC, indicating that H2AFZ-overexpressed HCC patients may be sensitive to immune checkpoint blockades (ICBs). Integrated analysis suggested that H2AFZhigh/TP53mut patients had the shortest OS and PFS time, but most likely to respond to ICBs. These findings indicate that the H2AFZ possesses potential value as a novel prognostic indicator for HCC patients and is correlated with immune infiltration in HCC, laying a foundation for future study of HCC investigation and intervention.
| S-EPMC8573175 | biostudies-literature
Project description:Lipid droplets, the intracellular storage organelles for neutral lipids, exist in a wide range of sizes and of morphologically distinct organization, from loosely dispersed lipid droplets to tightly packed lipid droplet clusters. We show that the lipid droplet protein AUP1 induces cluster formation. A fraction of AUP1 is monoubiquitinated at various lysine residues. This process depends on its internal CUE domain, which is a known ubiquitin-binding domain. AUP1 with a deleted or point mutagenized CUE domain, as well as a lysine-free mutant, are not ubiquitinated and do not induce lipid droplet clustering. When such ubiquitination deficient mutants are fused to ubiquitin, clustering is restored. AUP1 mutants with defective droplet targeting fail to induce clustering. Also, another lipid droplet protein, NSDHL, with a fused ubiquitin does not induce clustering. The data indicate that monoubiquitinated AUP1 on the lipid droplet surface specifically induces clustering, and suggest a homophilic interaction with a second AUP1 molecule or a heterophilic interaction with another ubiquitin-binding protein.
| S-EPMC3764060 | biostudies-literature
Project description:Sexual reproduction and clonality in eukaryotes are mostly seen as exclusive, the latter being rather exceptional. This view might be biased by focusing almost exclusively on metazoans. We analyze and discuss reproduction in the context of extant eukaryotic diversity, paying special attention to protists. We present results of phylogenetically extended searches for homologs of two proteins functioning in cell and nuclear fusion, respectively (HAP2 and GEX1), providing indirect evidence for these processes in several eukaryotic lineages where sex has not been observed yet. We argue that (i) the debate on the relative significance of sex and clonality in eukaryotes is confounded by not appropriately distinguishing multicellular and unicellular organisms; (ii) eukaryotic sex is extremely widespread and already present in the last eukaryotic common ancestor; and (iii) the general mode of existence of eukaryotes is best described by clonally propagating cell lines with episodic sex triggered by external or internal clues. However, important questions concern the relative longevity of true clonal species (i.e., species not able to return to sexual procreation anymore). Long-lived clonal species seem strikingly rare. We analyze their properties in the light of meiotic sex development from existing prokaryotic repair mechanisms. Based on these considerations, we speculate that eukaryotic sex likely developed as a cellular survival strategy, possibly in the context of internal reactive oxygen species stress generated by a (proto) mitochondrion. Thus, in the context of the symbiogenic model of eukaryotic origin, sex might directly result from the very evolutionary mode by which eukaryotic cells arose.
| S-EPMC4517231 | biostudies-literature
Project description:The Kinesin Family Member C1 (KIFC1) is highly expressed in a variety of tumors. Since it is linked with tumorigenesis and progression, KIFC1 has emerged as a promising candidate for targeted chemotherapies. Thus, this study aims to find out the association between KIFC1 and lung cancer. The original data were assessed from The Cancer Genome Atlas and Gene Expression Omnibus databases. Compared to normal lung tissues, both mRNA and protein levels of KIFC1 were significantly increased in lung cancer tissues. The upregulation of KIFC1 was significantly correlated with sex, pathological stage, and TMN stage. Survival analysis revealed that increased KIFC1 expression was associated with poor overall survival, first-progression survival and post-progression survival in lung cancer. Based on the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis, we observed that KIFC1 upregulation was linked to enrichment of the cell cycle and TP53 signaling pathway. Additionally, the overexpression of KIFC1 was positively correlated with TP53 mutations in lung cancer. Based on real-world cohort results, western blotting and RT-qPCR showed high-KIFC1 expression in lung cancer, which may be related to the malignancy of lung cancer. Finally, experiments in vitro showed that KIFC1 inhibitor could significantly inhibit the proliferation and invasion of lung cancer cells. In conclusion, KIFC1 is a poor prognostic biomarker, and patients with high-KIFC1 levels may benefit from targeted therapy.
| S-EPMC10919520 | biostudies-literature
Project description:The recently discovered endoplasmic reticulum (ER) membrane protein complex (EMC) has been implicated in ER-associated degradation (ERAD), lipid transport and tethering between the ER and mitochondrial outer membranes, and assembly of multipass ER-membrane proteins. The EMC has been studied in both animals and fungi but its presence outside the Opisthokont clade (animals + fungi + related protists) has not been demonstrated. Here, using homology-searching algorithms, I show that the EMC is truly an ancient and conserved protein complex, present in every major eukaryotic lineage. Very few organisms have completely lost the EMC, and most, even over 2 billion years of eukaryote evolution, have retained a majority of the complex members. I identify Sop4 and YDR056C in Saccharomyces cerevisiae as Emc7 and Emc10, respectively, subunits previously thought to be specific to animals. This study demonstrates that the EMC was present in the last eukaryote common ancestor (LECA) and is an extremely important component of eukaryotic cells even though its primary function remains elusive.
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Project description:Immune checkpoint inhibitors (ICIs), is characterized by durable responses and improved survival in non-small cell lung cancer (NSCLC). However, there is a lack of predictive biomarkers to optimize the use of ICIs in cancers. The clinical benefit of patients with lung adenocarcinoma (LUAD) harboring TP53 mutations undergoing conventional treatments need to be optimized. Recently, studies indicated that TP53 mutations may be associated with improved survival in patients treated with ICIs. The immunotherapy cohort was used to estimate the association of TP53 mutations with the immune prognosis of LUAD. Genomic data were used to estimate the difference in immunogenicity and mutations in DNA damage repair (DDR). Clinical and genomic data were collected from patients with LUAD treated with ICIs and profiled using panel. The Cancer Genome Atlas (TCGA)-LUAD cohort was used to distinguish the tumor microenvironment, mutational profiles, immunogenicity and DDR mutations between TP53-mutated and TP53-wild-type. In the MSKCC-LUAD cohort, TP53-mutated LUAD showed significantly prolonged progression-free survival (PFS) (P = 0.017, HR = 0.69 [95%CI: 0.50-0.94]). CIBERSORT suggested that TP53-mutated had a higher proportion of activated immune cell infiltration. Additionally, TP53-mutated LUAD had higher expression levels of chemokines and proinflammatory mediators, increased tumor burden, neoantigen load, and DDR mutations. Gene set enrichment analysis (GSEA) suggests that TP53-mutated LUAD is significantly enriched in the cell cycle and DDR pathway but significantly downregulated in lipid metabolism. Our findings suggested that TP53 mutation may be a potential biomarker of immunotherapy for LUAD.
| S-EPMC7710974 | biostudies-literature
Project description:Numerous studies have tested the association between TP53 mutations in ovarian cancer and prognosis but these have been consistently confounded by limitations in study design, methodology, and/or heterogeneity in the sample cohort. High-grade serous (HGS) carcinoma is the most clinically important histological subtype of ovarian cancer. As these tumours may arise from the ovary, Fallopian tube or peritoneum, they are collectively referred to as high-grade pelvic serous carcinoma (HGPSC). To identify the true prevalence of TP53 mutations in HGPSC, we sequenced exons 2-11 and intron-exon boundaries in tumour DNA from 145 patients. HGPSC cases were defined as having histological grade 2 or 3 and FIGO stage III or IV. Surprisingly, pathogenic TP53 mutations were identified in 96.7% (n = 119/123) of HGPSC cases. Molecular and pathological review of mutation-negative cases showed evidence of p53 dysfunction associated with copy number gain of MDM2 or MDM4, or indicated the exclusion of samples as being low-grade serous tumours or carcinoma of uncertain primary site. Overall, p53 dysfunction rate approached 100% of confirmed HGPSCs. No association between TP53 mutation and progression-free or overall survival was found. From this first comprehensive mapping of TP53 mutation rate in a homogeneous group of HGPSC patients, we conclude that mutant TP53 is a driver mutation in the pathogenesis of HGPSC cancers. Because TP53 mutation is almost invariably present in HGPSC, it is not of substantial prognostic or predictive significance.
| S-EPMC3262968 | biostudies-literature