28 research outputs found
Multi-Omics Integration-Based Prioritisation of Competing Endogenous RNA Regulation Networks in Small Cell Lung Cancer : Molecular Characteristics and Drug Candidates
BackgroundThe competing endogenous RNA (ceRNA) network-mediated regulatory mechanisms in small cell lung cancer (SCLC) remain largely unknown. This study aimed to integrate multi-omics profiles, including the transcriptome, regulome, genome and pharmacogenome profiles, to elucidate prioritised ceRNA characteristics, pathways and drug candidates in SCLC. MethodWe determined the plasma messenger RNA (mRNA), microRNA (miRNA), long noncoding RNA (lncRNA) and circular RNA (circRNA) expression levels using whole-transcriptome sequencing technology in our SCLC plasma cohort. Significantly expressed plasma mRNAs were then overlapped with the Gene Expression Omnibus (GEO) tissue mRNA data (GSE 40275, SCLC tissue cohort). Next, we applied a multistep multi-omics (transcriptome, regulome, genome and pharmacogenome) integration analysis to first construct the network and then to identify the lncRNA/circRNA-miRNA-mRNA ceRNA characteristics, genomic alterations, pathways and drug candidates in SCLC. ResultsThe multi-omics integration-based prioritisation of SCLC ceRNA regulatory networks consisted of downregulated mRNAs (CSF3R/GAA), lncRNAs (AC005005.4-201/DLX6-AS1-201/NEAT1-203) and circRNAs (hsa_HLA-B_1/hsa_VEGFC_8) as well as upregulated miRNAs (hsa-miR-4525/hsa-miR-6747-3p). lncRNAs (lncRNA-AC005005.4-201 and NEAT1-203) and circRNAs (circRNA-hsa_HLA-B_1 and hsa_VEGFC_8) may regulate the inhibited effects of hsa-miR-6747-3p for CSF3R expression in SCLC, while lncRNA-DLX6-AS1-201 or circRNA-hsa_HLA-B_1 may neutralise the negative regulation of hsa-miR-4525 for GAA in SCLC. CSF3R and GAA were present in the genomic alteration, and further identified as targets of FavId and Trastuzumab deruxtecan, respectively. In the SCLC-associated pathway analysis, CSF3R was involved in the autophagy pathways, while GAA was involved in the glucose metabolism pathways. ConclusionsWe identified potential lncRNA/cirRNA-miRNA-mRNA ceRNA regulatory mechanisms, pathways and promising drug candidates in SCLC, providing novel potential diagnostics and therapeutic targets in SCLC.Peer reviewe
Role of non-coding RNA networks in leukemia progression, metastasis and drug resistance.
Early-stage detection of leukemia is a critical determinant for successful treatment of the disease and can increase the survival rate of leukemia patients. The factors limiting the current screening approaches to leukemia include low sensitivity and specificity, high costs, and a low participation rate. An approach based on novel and innovative biomarkers with high accuracy from peripheral blood offers a comfortable and appealing alternative to patients, potentially leading to a higher participation rate.Recently, non-coding RNAs due to their involvement in vital oncogenic processes such as differentiation, proliferation, migration, angiogenesis and apoptosis have attracted much attention as potential diagnostic and prognostic biomarkers in leukemia. Emerging lines of evidence have shown that the mutational spectrum and dysregulated expression of non-coding RNA genes are closely associated with the development and progression of various cancers, including leukemia. In this review, we highlight the expression and functional roles of different types of non-coding RNAs in leukemia and discuss their potential clinical applications as diagnostic or prognostic biomarkers and therapeutic targets
Noncoding RNA in cholangiocarcinoma
Cholangiocarcinomas (CCAs) are tumors with a dismal prognosis. Early diagnosis is a key challenge because of the lack of specific symptoms, and the curability rate is low due to the difficulty in achieving a radical resection and the intrinsic chemoresistance of CCA cells. Noncoding RNAs (ncRNAs) are transcripts that are not translated into proteins but exert their functional role by regulating the transcription and translation of other genes. The discovery of the first ncRNA dates back to 1993 when the microRNA (miRNA) lin-4 was discovered in Caenorhabditis elegans. Only 10 years later, miRNAs were shown to play an oncogenic role in cancer cells and within 20 years miRNA therapeutics were tested in humans. Here, the authors review the latest evidence for a role for ncRNAs in CCA and discuss the promise and challenges associated with the introduction of ncRNAs into clinical practice
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic autoimmune disease generating joint pain and damage in which inflammation plays a major role. RA joints are inflamed and stiff. Symptoms include joint swelling and warmth causing fatigue affecting life’s health-related quality. Still, there are many other medical conditions that can also be associated with your symptoms and signs. This book is not a substitute for a diagnosis from a healthcare provider. Yet, understanding your symptoms and signs and educating yourself about health conditions is important and can contribute to having the healthiest possible life. Herein, Professor Hechmi Toumi offers an edited volume with detailed new information on RA pathogenesis and explains both approaches and treatment options: recent clinical research and traditional methods
Role of miRNAs in Cancer
MicroRNAs are the best representatives of the non-coding part of the genome and their functions are mostly linked to their target genes. During the process of carcinogenesis, both dysregulation of microRNAs and their target genes can explain the development of the disease. However, most of the target genes of microRNAs have not yet been elucidated. In this book, we add new information related to the functions of microRNAs in various tumors and their associated targetome
Overcoming drug resistance: targeting the BCL-2 family and the long non-coding RNA HCP5 in medulloblastoma and colorectal cancer
Colorectal cancer (CRC) is one of the most common cancers in the UK and medulloblastoma is a common cancer found in children. While there has been a progressive improvement in treatment outcomes, success has been marred by drug resistance and severe side effects. Therefore, this project focused on two aspects of chemotherapeutic drug resistance, the first using the antimitotic agent vincristine in combination with inhibitors of the anti-apoptotic Bcl-2 family proteins, while the second investigated the role of the long non-coding RNA (lncRNA), HCP5 in the resistance of cells to genotoxic agents. In the first part, three medulloblastoma cell lines (DAOY, MB03, ONS76) were analysed for the expression of Bcl-xL and ONS76 cells found to have the highest level of this anti-apoptotic protein. Subsequent results indicated that Bcl-xL encourages mitotic slippage and stemness and that knockdown of Bcl-xL in the high expressing ONS76 cells, reduces these and sensitizes the cells to the anti-mitotic agent vincristine. Thus, pharmacological inhibition of Bcl-xL should sensitize medulloblastoma cells to low doses of vincristine. Regarding the lncRNA HCP5, results showed that HCP5 was generally more highly expressed in a panel of CRC cell lines than the three medulloblastoma cell lines, corroborating data from an in-silico analysis for the corresponding tumours. One function of HCP5 is to translocate the multifunctional YB-1 protein from the cytoplasm to the nucleus where it carries out many of its functions. Knockdown of HCP5 followed by immunofluorescence indicated a reduction in the amount of YB-1 in the nucleus, confirming this function. Subsequently, HCP5 silencing sensitized all cell lines tested to the DNA damaging agents, cisplatin, oxaliplatin and tert-butyl hydroperoxide and also resulted in an increase in double-strand breaks as determined by H2AX formation. Finally, fluorescence activated cell sorting using Annexin V and propidium iodide confirmed a decrease in cell viability in HCP5 knockdown cells following treatment with genotoxic agents and that this was mirrored by an increased apoptotic fraction. Together, these studies indicate the possibilities of using novel therapeutics to increase the functionality of existing treatments to combat acquired drug resistance in cancer patients
MicroRNA in Solid Tumor and Hematological Diseases
MicroRNAs (miRNAs), which are a type of short non-coding RNA, are involved in number of processes, such as differentiation, development, inflammation, immune response, and cancer. miRNAs, which act as oncogenes or tumor suppressor genes, can control and regulate the translation and stability of target messenger RNA, contributing to cancer pathogenesis. Despite the progress that has been made in discovering the mechanisms of how miRNAs function in tumors, many questions and aspects of miRNA biology and processing still remain to be determined. This Special Issue, titled “MicroRNA in Solid Tumor and Hematological Diseases”, provides a panorama of the existing knowledge gaps and potential uses of microRNAs to predict clinical outcome or response to therapies and provides evidence to explain their role as biomarkers to modulate the biological pathways that are critical for cancer development and progression. It includes eleven peer-reviewed papers that cover the role of microRNAs in different tumor types and their potential applications in diagnosis and clinical approaches
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Primary sclerosing cholangitis: from genetic risk to disease biology
Primary sclerosing cholangitis: from genetic risk to disease biology
Elizabeth Claire Goode
One in 10,000 people in the Western world lives with Primary Sclerosing Cholangitis (PSC), an immune-mediated, inflammatory disease of the bile ducts that is highly co-morbid with inflammatory bowel disease (IBD). PSC confers risk of serious disease sequelae including hepatobiliary malignancy and progression to end-stage liver failure, for which the
only treatment option is liver transplantation. The absence of effective medical therapies for PSC reflects our current limited understanding of the disease’s aetiology and pathogenesis.
Our DNA, laid down at conception, gives us an unrivalled opportunity to understand the underlying causal biology of disease. This is because the genetic variants associated with disease susceptibility perturb genes and biological pathways that contribute to disease causality. Twenty-two regions of the genome, outside of the HLA, have been associated with PSC risk. These loci offer the potential for huge insight into the causal biology of PSC, if only we can robustly identify the true causal variants driving these loci and the genes they perturb. However, this is complicated by several scientific challenges. Firstly, the majority of disease-associated risk loci occur within non-coding regions of the genome. Secondly, patterns of correlation between variants within a risk locus means that the true causal variant driving the signal could be any of those highly correlated with the variant with the smallest p-value.
In this thesis, I present analyses aimed at identifying the true genes and causal variants underlying each of the twenty-two PSC risk loci. Many non-coding risk variants associated with complex disease exert a quantitative affect upon gene expression i.e. are expression quantitative trait loci (eQTLs). Colocalisation assesses the evidence that a single shared
causal variant is responsible for driving PSC risk and gene expression via an eQTL. In order to assign dysregulated genes to PSC risk loci, I perform colocalisation with eQTLs mapped in multiple cell-types and tissues mechanistically relevant to PSC. Because PSC is rare, eQTLs have not previously been mapped in all cell-types most relevant to this disease. In
addition, I therefore map eQTLs in six peripheral blood T-cell subsets (including the rare CCR9+ gut-homing T-cells) from 80 patients with PSC and IBD. With colocalisation, I assign causal genes to five PSC risk loci, and assign other epigenetic regulatory features including methylation or histone modification, to six risk loci. Statistical fine-mapping of each risk locus in both the GWAS and eQTL data enables me to resolve three PSC risk loci to a single causal variant and nine loci to 95% credible sets containing ten or fewer variants.
The results presented in this thesis identify three genes (PRKD2, ETS2 and UBASH3A), causal in the pathogenesis of PSC, which are currently the target of existing or experimental therapeutic agents. Firstly, reduced expression of PRKD2 causes excessive cell-autonomous T-follicular helper cell development and B-cell activation, and is associated with increased
risk of PSC. Several studies are investigating the therapeutic effects of increasing the kinase activity of PRKD2. ETS2 is involved in the induction of pro-inflammatory cytokine release from macrophages and IL-2 regulation in Th to Th0 transition. ETS2 inhibitors are currently the subject of early therapeutic trials. Finally, UBASH3A attenuates the
NF-kB/I-KKb pathway, an inflammatory pathway that is already targeted by proteasome inhibitors and acetylsalicylic acid, both of which could be potentially therapeutic in PSC.
PSC is a debilitating disease with serious disease sequelae, for which new therapeutic options are urgently needed. In this thesis, I elucidate multiple genes with a causal role in PSC pathogenesis, several of which are potential candidates for future therapeutic target