S100 calcium binding protein A6 and associated long noncoding ribonucleic acids as biomarkers in the diagnosis and staging of primary biliary cholangitis.
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ABSTRACT:
SUBMITTER: Dong XH
PROVIDER: S-EPMC8108032 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundDue to their inherent role in cell function, long non-coding ribonucleic acids (lncRNAs) mediate changes in the microenvironment, and thereby participate in the development of cellular senescence.AimsThis study aimed to identify cellular senescence-related lncRNAs that could predict the prognosis of liver cancer.Methods and resultsGene expression and clinical data were downloaded from the UCSC Xena platform, ICGC, and TCGA databases. Cox regression and LASSO regression were used to establish a cellular senescence-related lncRNA model. ROC curves and Kaplan-Meier survival curves were then constructed to predict patient prognosis. Cox regression analysis and clinical characteristics were used to evaluate the capability of the model. Tumor mutational burden and tumor-infiltrating immune cell analyses were subsequently performed in the risk subgroups and the samples in the entire cohort were reclustered. Finally, potential small molecule immune-targeted drugs were identified based on the model. The cellular senescence-related prognostic model that was constructed based on AGAP11 and FAM182B. Along with the results of Cox regression and Lasso regression, the risk score was found to be an independent factor for predicting overall survival in cohorts. In the subgroup analysis, the prognosis of the low-risk group in each cohort was significantly higher than that of the high-risk group; the area under temporal ROC curves and clinical ROC curves were all greater than 0.65, respectively. C-index shows that the risk scores are greater than 0.6, showing the stability of the model. The high-risk group demonstrated lower tumor microenvironment and higher tumor mutational burden scores, further verifying the reliability of the model grouping results. Analysis of tumor-infiltrating immune cells indicated that CD8+ and γδ T cells were more abundant among patients in the low-risk group; cluster reorganization indicated that the two groups had different prognoses and proportions of immune cells. The p value of potential drugs predicted based on the expression of model lncRNAs were all less than .05, demonstrating the potential of model lncRNAs as therapeutic targets to some extent.ConclusionA prognostic model based on cellular senescence-associated lncRNAs was established and this may be used as a potential biomarker for the prognosis assessment of liver cancer patients.
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Project description:The pathogenesis of pancreatic ductal adenocarcinoma (PDAC) remains poorly understood. S100 calcium-binding protein A6 (S100A6) has been associated with PDAC; however, the effect of S100A6 on PDAC migration and invasion has not yet been explored. In this study, Panc-1 cells were transfected with a plasmid to induce overexpression of S100A6, and β-catenin was knocked down using a specific short hairpin RNA (shRNA). The wound-healing and Transwell assays demonstrated that S100A6 promoted PDAC cell migration and invasion. Furthermore, β-catenin shRNA inhibited the migration and invasion of PDAC cells. We confirmed that S100A6 induces PDAC cell migration and invasion via activation of β-catenin in vitro. Assessment of mRNA and protein levels revealed that S100A6 induces increased expression of β-catenin, N-cadherin and vimentin, and decreased expression of E-cadherin in PDAC cells. β-catenin shRNA also altered the expression of epithelial-mesenchymal transition (EMT)-related markers in PDAC cells. Specifically, expression of E-cadherin was increased, whereas expression of N-cadherin and vimentin was decreased. Finally, we demonstrated that S100A6 alters the expression of EMT-related markers via β-catenin activation. In conclusion, S100A6 induces EMT and promotes cell migration and invasion in a β-catenin-dependent manner. S100A6 may therefore represent a novel potential therapeutic target for the treatment of pancreatic cancer.
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Project description:Multiple sclerosis (MS) is a chronic fatal central nervous system (CNS) disease involving in complex immunity dysfunction. Recently, long noncoding RNAs (lncRNAs) were discovered as the important regulatory factors for the pathogenesis of MS. However, these findings often cannot be repeated and confirmed by the subsequent studies. We considered that the small-scale samples or the heterogeneity among various tissues may result in the divergence of the results. Currently, RNA-seq has become a powerful approach to quantify the abundances of lncRNA transcripts. Therefore, we comprehensively collected the MS-related RNA-seq data from a variety of previous studies, and integrated these data using an expression-based meta-analysis to identify the differentially expressed lncRNA between MS patients and controls in whole samples and subgroups. Then, we performed the Jensen-Shannon (JS) divergence and cluster analysis to explore the heterogeneity and expression specificity among various tissues. Finally, we investigated the potential function of identified lncRNAs for MS using weighted gene co-expression network analysis (WGCNA) and gene set enrichment analysis (GSEA), and 5,420 MS-related lncRNAs specifically expressed in the brain tissue were identified. The subgroup analysis found a small heterogeneity of the lncRNA expression profiles between brain and blood tissues. The results of WGCNA and GSEA showed that a potential important function of lncRNAs in MS may be involved in the regulation of ribonucleoproteins and tumor necrosis factor cytokines receptors. In summary, this study provided a strategy to explore disease-related lncRNAs on genome-wide scale, and our findings will be benefit to improve the understanding of MS pathogenesis.
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Project description:Purpose of reviewPrimary biliary cholangitis (PBC) is characterized by autoimmune damage of intrahepatic bile ducts associated with a loss of tolerance to mitochondrial antigens. PBC etiopathogenesis is intriguing because of different perplexing features, namely: a) although mitochondria are present in all cell types and tissues, the damage is mainly restricted to biliary epithelial cells (BECs); b) despite being an autoimmune disorder, it does not respond to immunosuppressive drugs but rather to ursodeoxycholic acid, a bile salt that induces HCO3- rich choleresis; c) the overwhelming female preponderance of the disease remains unexplained. Here we present an etiopathogenic view of PBC which sheds light on these puzzling facts of the disease.Recent findingsPBC develops in patients with genetic predisposition to autoimmunity in whom epigenetic mechanisms silence the Cl-/HCO3- exchanger AE2 in both cholangiocytes and lymphoid cells. Defective AE2 function can produce BECs damage as a result of decreased biliary HCO3- secretion with disruption of the protective alkaline umbrella that normally prevents the penetration of toxic apolar bile salts into cholangiocytes. AE2 dysfunction also causes increased intracellular pH (pHi) in cholangiocytes, leading to the activation of soluble adenylyl cyclase, which sensitizes BECs to bile salt-induced apoptosis. Recently, mitophagy was found to be inhibited by cytosolic alkalization and stimulated by acidification. Accordingly, we propose that AE2 deficiency may disturb mitophagy in BECs, thus, promoting the accumulation of defective mitochondria, oxidative stress and presentation of mitochondrial antigens to the immune cells. As women possess a more acidic endolysosomal milieu than men, mitophagy might be more affected in women in an AE2-defective background. Apart from affecting BECs function, AE2 downregulation in lymphocytes may also contribute to alter immunoregulation facilitating autoreactive T-cell responses.SummaryPBC can be considered as a disorder of Cl-/HCO3- exchange in individuals with genetic predisposition to autoimmunity.
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Project description:Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a model autoimmune disease with chronic cholestasis characterized by the hallmark of anti-mitochondrial antibodies and treated with ursodeoxycholic acid (UDCA). However, approximately 20-40% of patients incompletely respond to UDCA and have an increased risk of disease progression. Although there have been significant advances in the immunobiology of PBC, these have yet to be translated into newer therapeutic modalities. Current approaches to controlling the immune response include broad immunosuppression with corticosteroids as well as targeted therapies directed against T and B cells. In contrast, ameliorating cholestasis is the focus of other therapies in development, including obeticholic acid. In this article the authors will discuss ongoing clinical trials and, in particular, the rationale for choosing agents that may effectively target the aberrant immune response.
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Project description:Primary biliary cholangitis (PBC) causes chronic and persistent cholestasis in the liver, eventually resulting in cirrhosis and hepatic failure without appropriate treatment. PBC mainly develops in middle-aged women, but it is also common in young women and men. PBC is considered a model of autoimmune disease because of the presence of diseasespecific autoantibodies, that is, antimitochondrial antibodies (AMAs), intense infiltration of mononuclear cells into the bile ducts, and a high prevalence of autoimmune diseases such as comorbidities. Histologically, PBC is characterized by degeneration and necrosis of intrahepatic biliary epithelial cells surrounded by a dense infiltration of mononuclear cells, coined as chronic non-suppurative destructive cholangitis, which leads to destructive changes and the disappearance of small- or medium-sized bile ducts. Since 1990, early diagnosis with the detection of AMAs and introduction of ursodeoxycholic acid as first-line treatment has greatly altered the clinical course of PBC, and liver transplantation-free survival of patients with PBC is now comparable to that of the general population.
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Project description:Primary biliary cholangitis (PBC) is a rare autoimmune cholestatic liver disease that may progress to fibrosis and/or cirrhosis. Treatment options are currently limited. The first-line therapy for this disease is the drug ursodeoxycholic acid (UDCA), which has been proven to normalize serum markers of liver dysfunction, halt histologic disease progression, and lead to a prolongation of transplant-free survival. However, 30-40% of patients unfortunately do not respond to this first-line therapy. Obeticholic acid (OCA) is the only registered agent for second-line treatment in UDCA-non responders. In this review, we focus on the pharmacological features of OCA, describing its mechanism of action of and its tolerability and efficacy in PBC patients. We also highlight current perspectives on future therapies for this condition.
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Project description:Noncoding RNA (ncRNA) is a kind of RNA that plays an important role in many biological processes, diseases, and cancers, while cannot translate into proteins. With the development of next-generation sequence technology, thousands of novel RNAs with long open reading frames (ORFs, longest ORF length > 303 nt) and short ORFs (longest ORF length ? 303 nt) have been discovered in a short time. How to identify ncRNAs more precisely from novel unannotated RNAs is an important step for RNA functional analysis, RNA regulation, etc. However, most previous methods only utilize the information of sequence features. Meanwhile, most of them have focused on long-ORF RNA sequences, but not adapted to short-ORF RNA sequences. In this paper, we propose a new reliable method called NCResNet. NCResNet employs 57 hybrid features of four categories as inputs, including sequence, protein, RNA structure, and RNA physicochemical properties, and introduces feature enhancement and deep feature learning policies in a neural net model to adapt to this problem. The experiments on benchmark datasets of 8 species shows NCResNet has higher accuracy and higher Matthews correlation coefficient (MCC) compared with other state-of-the-art methods. Particularly, on four short-ORF RNA sequence datasets, specifically mouse, Saccharomyces cerevisiae, zebrafish, and cow, NCResNet achieves greater than 10 and 15% improvements over other state-of-the-art methods in terms of accuracy and MCC. Meanwhile, for long-ORF RNA sequence datasets, NCResNet also has better accuracy and MCC than other state-of-the-art methods on most test datasets. Codes and data are available at https://github.com/abcair/NCResNet.
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Project description:Long non-coding RNAs (lncRNAs) regulate many biological processes in plants, including defense against pathogens and herbivores. Recently, many small ORFs embedded in lncRNAs have been identified to encode biologically functional peptides (small ORF-encoded peptides [SEPs]) in many species. However, it is unknown whether lncRNAs mediate defense against herbivore attack and whether there are novel functional SEPs for these lncRNAs. By sequencing Spodoptera litura-treated leaves at six time-points in Nicotiana tabacum, 22,436 lncRNAs were identified, of which 787 were differentially expressed. Using a comprehensive mass spectrometry (MS) pipeline, 302 novel SEPs derived from 115 tobacco lncRNAs were identified. Moreover, 61 SEPs showed differential expression after S. litura attack. Importantly, several of these peptides were characterized through 3D structure prediction, subcellular localization validation by laser confocal microscopy, and western blotting. Subsequent bioinformatic analysis revealed some specific chemical and physical properties of these novel SEPs, which probably represent the largest number of SEPs identified in plants to date. Our study not only identifies potential lncRNA regulators of plant response to herbivore attack but also serves as a valuable resource for the functional characterization of SEP-encoding lncRNAs.
| S-EPMC9538394 | biostudies-literature
Project description:Primary biliary cholangitis (PBC) is a rare chronic cholestatic liver disease that may progress to biliary cirrhosis if left untreated. The first-line therapy for PBC is ursodeoxycholic acid (UDCA). Unfortunately, 1 of 3 patients does not respond to UDCA. These patients are at risk for developing clinical events, including cirrhosis, complications of portal hypertension, hepatocellular carcinoma, liver transplant, or death. Recently, the U.S. Food and Drug Administration approved obeticholic acid to be used in certain patients with PBC. Off-label therapies are also used, and several other therapies are currently under evaluation. Real-world effectiveness of newly approved and off-label therapies remains unknown. TARGET-PBC is a 5-year, longitudinal, observational study of patients with PBC that will evaluate the effectiveness of clinical practice interventions and provide practical information unobtainable in registration trials. Enrollment will take place at both academic and community sites. In addition to consenting to medical records review, participants will be asked to provide an annual blood sample and complete patient reported outcome surveys at predetermined intervals. Any available liver biopsies will be digitally preserved. Conclusion: Key study outcomes will be the evaluation of the safety and effectiveness of PBC interventions and the assessment of disease progression under real-world conditions. (Hepatology Communications 2018;2:484-491).
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