The Roles of Alternative Splicing in Tumor-immune Cell Interactions.
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ABSTRACT:
SUBMITTER: Wang Y
PROVIDER: S-EPMC8388066 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Two major posttranscriptional mechanisms-alternative splicing (AS) and alternative polyadenylation (APA)-have attracted much attention in cancer research. Nevertheless, their roles in clear cell renal carcinoma (ccRCC) are still ill defined. Herein, this study was conducted to uncover the implications of AS and APA events in ccRCC progression. Through consensus molecular clustering analysis, two AS or APA RNA processing phenotypes were separately constructed with distinct prognosis, tumor-infiltrating immune cells, responses to immunotherapy, and chemotherapy. The AS or APA score was constructed to quantify AS or APA RNA processing patterns of individual ccRCCs with principal-component analysis. Both high AS and APA scores were characterized by undesirable survival outcomes, relatively high response to immunotherapy, and low sensitivity to targeted drugs, such as sorafenib and pazopanib. Moreover, several small molecular compounds were predicted for patients with a high AS or APA score. There was a positive correlation between AS and APA scores. Their interplay contributed to poor prognosis and reshaped the tumor immune microenvironment. Collectively, this study is the first to comprehensively analyze two major posttranscriptional events in ccRCC. Our findings uncovered the potential functions of AS and APA events and identified their therapeutic potential in immunotherapy and targeted therapy.
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Project description:Alternative RNA splicing (ARS) is an essential and tightly regulated cellular process of post-transcriptional regulation of pre-mRNA. It produces multiple isoforms and may encode proteins with different or even opposite functions. The dysregulated ARS of pre-mRNA contributes to the development of many cancer types, including oral squamous cell carcinoma (OSCC), and may serve as a biomarker for the diagnosis and prognosis of OSCC and an attractive therapeutic target. ARS is mainly regulated by splicing factors, whose expression is also often dysregulated in OSCC and involved in tumorigenesis. This review focuses on the expression and roles of splicing factors in OSCC, the alternative RNA splicing events associated with OSCC, and recent advances in therapeutic approaches that target ARS.
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Project description:BackgroundOral squamous cell carcinoma (OSCC) is the most prevalent malignant tumor in head and neck region. Platinum drug resistance limits the clinical application of chemotherapy regardless of medical development. The aim of our study is to identify cisplatin-resistant genes which can be used as new therapeutic targets and investigate the functional mechanism of OSCC chemoresistance.MethodsThe OSCC Cal27 and HSC4 cisplatin-resistant cell lines were constructed to screen the differential genes/transcripts expression. GO, KEGG and GSEA were performed to reveal the relevant signaling pathways. Alternative splicing (AS) software rMATs was applied to explore AS events in chemoresistance. R package and TIMER tools were used to evaluate the linear correlation between CD44 and immune cell subpopulations. The co-culture model of dendritic cells (DCs) and OSCC cells was applied to explore the effect of CD44 on immune microenvironment and cisplatin resistance.ResultsOur results showed that CD44 was differentially expressed in cisplatin-resistant OSCC cells. Through bioinformatics prediction and experimental verification, we confirmed that CD44 occurring AS was involved in tumor progression and cisplatin resistance. Moreover, CD44 could further enhance the cisplatin resistance of OSCC by activating DCs, making CD44 to be a potential intervention target. We also identified DC as a new target for platinum drugs to stimulate the growth of OSCC.ConclusionOur findings not only make it possible to explore new therapeutic methods, such as CD44 inhibitors or antisense oligonucleotides, but also provide insights into the new mechanisms of cisplatin resistance to chemotherapy.
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Project description:Alternative splicing (AS) disruption has been linked to disorders of muscle development, as well as muscular atrophy. However, the precise changes in AS patterns that occur during myogenesis are not well understood. Here, we employed isoform long-reads RNA-seq (Iso-seq) and single-cell RNA-seq (scRNA-seq) to investigate the AS landscape during myogenesis. Our Iso-seq data identified 61,146 full-length isoforms representing 11,682 expressed genes, of which over 52% were novel. We identified 38,022 AS events, with most of these events altering coding sequences and exhibiting stage-specific splicing patterns. We identified AS dynamics in different types of muscle cells through scRNA-seq analysis, revealing genes essential for the contractile muscle system and cytoskeleton that undergo differential splicing across cell types. Gene-splicing analysis demonstrated that AS acts as a regulator, independent of changes in overall gene expression. Two isoforms of splicing factor TRA2B play distinct roles in myogenic differentiation by triggering AS of TGFBR2 to regulate canonical TGF-β signalling cascades differently. Our study provides a valuable transcriptome resource for myogenesis and reveals the complexity of AS and its regulation during myogenesis.
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Project description:The extent of and the oncogenic role played by alternative splicing (AS) in cancer are well documented. Nonetheless, only few studies have attempted to dissect individual gene function at an isoform level. Here, we focus on the AS of splicing factors during prostate cancer progression, as these factors are known to undergo extensive AS and have the potential to affect hundreds of downstream genes. We identified exon 7 (ex7) in the MBNL1 (Muscleblind-like 1) transcript as being the most differentially included exon in cancer, both in cell lines and in patients' samples. In contrast, MBNL1 overall expression was down-regulated, consistently with its described role as a tumor suppressor. This observation holds true in the majority of cancer types analyzed. We first identified components associated to the U2 splicing complex (SF3B1, SF3A1, and PHF5A) as required for efficient ex7 inclusion and we confirmed that this exon is fundamental for MBNL1 protein homodimerization. We next used splice-switching antisense oligonucleotides (AONs) or siRNAs to compare the effect of MBNL1 splicing isoform switching with knockdown. We report that whereas the absence of MBNL1 is tolerated in cancer cells, the expression of isoforms lacking ex7 (MBNL1 ?ex7) induces DNA damage and inhibits cell viability and migration, acting as dominant negative proteins. Our data demonstrate the importance of studying gene function at the level of alternative spliced isoforms and support our conclusion that MBNL1 ?ex7 proteins are antisurvival factors with a defined tumor suppressive role that cancer cells tend to down-regulate in favor of MBNL +ex7 isoforms.
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Project description:The anti-tumor activity of the immune system is increasingly recognized as critical for the mounting of a prolonged and effective response to cancer growth and invasion, and for preventing recurrence following resection or treatment. As the knowledge of tumor-immune cell interactions has advanced, experimental investigation has been complemented by mathematical modeling with the goal to quantify and predict these interactions. This succinct review offers an overview of recent tumor-immune continuum modeling approaches, highlighting spatial models. The focus is on work published in the past decade, incorporating one or more immune cell types and evaluating immune cell effects on tumor progression. Due to their relevance to cancer, the following immune cells and their combinations are described: macrophages, Cytotoxic T Lymphocytes, Natural Killer cells, dendritic cells, T regulatory cells, and CD4+ T helper cells. Although important insight has been gained from a mathematical modeling perspective, the development of models incorporating patient-specific data remains an important goal yet to be realized for potential clinical benefit.
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Project description:This dataset contains the global and terminal proteome of THP-1 and LCL cell lines untreated or treated with phorbol 12-myristate 13-acetate (PMA) and interferon-α2 (IFN-α2), respectively. Extracted proteins were digested with trypsin or V8 protease and protein terminal peptides were isolated with strong cation exchange chromatography or metal oxide-based ligand-exchange chromatography. All peptides were labeled with TMT-tag, and a total of 16 channels were used with quadruplicates of untreated LCL, IFN-α2-treated LCL, untreated THP-1, and PMA-treated THP-1 peptides, respectively. The labeled peptides were fractionated into 24 vials by reversed-phase HPLC at high pH conditions.
2024-04-08 | PXD040962 | JPOST Repository
Project description:SOX9 is known as a crucial transcription factor for various developmental processes and for tissue homeostasis. We examined here its potential role in alternative splicing by analyzing global splicing changes, using RNA-seq of colon tumor cells. We show that SOX9 knockdown alters the splicing of hundreds of genes without affecting their expression levels, revealing that SOX9 controls distinct splicing and transcriptional programs. SOX9 does not affect splicing patterns through the control of splicing factors expression. We identify mutants that uncouple SOX9 splicing function from its transcriptional activity. We demonstrate that SOX9 binds to RNA and associates with several RNA-binding proteins, including the core exon junction complex component Y14. Half of SOX9 splicing targets are also modulated by Y14 and are no longer regulated by SOX9 upon Y14 depletion. Altogether, our work reveals that SOX9 is a moonlighting protein which modulates either transcription or splicing of distinct sets of targets.
| S-EPMC6158501 | biostudies-literature
Project description:Homeostatic plasticity refers to the ability of neuronal networks to stabilize their activity in the face of external perturbations. Most forms of homeostatic plasticity ultimately depend on changes in the expression or activity of ion channels and synaptic proteins, which may occur at the gene, transcript, or protein level. The most extensively investigated homeostatic mechanisms entail adaptations in protein function or localization following activity-dependent posttranslational modifications. Numerous studies have also highlighted how homeostatic plasticity can be achieved by adjusting local protein translation at synapses or transcription of specific genes in the nucleus. In comparison, little attention has been devoted to whether and how alternative splicing (AS) of pre-mRNAs underlies some forms of homeostatic plasticity. AS not only expands proteome diversity but also contributes to the spatiotemporal dynamics of mRNA transcripts. Prominent in the brain where it can be regulated by neuronal activity, it is a flexible process, tightly controlled by a multitude of factors. Given its extensive use and versatility in optimizing the function of ion channels and synaptic proteins, we argue that AS is ideally suited to achieve homeostatic control of neuronal output. We support this thesis by reviewing emerging evidence linking AS to various forms of homeostatic plasticity: homeostatic intrinsic plasticity, synaptic scaling, and presynaptic homeostatic plasticity. Further, we highlight the relevance of this connection for brain pathologies.
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Project description:BackgroundAlternative splicing (AS), a pivotal post-transcriptional process across more than 95% of human transcripts, is involved in transcript structural variations and protein complexity. Clinical implications of AS events and their interaction with tumor immunity were systematically analyzed in lung adenocarcinoma (LUAD).MethodsTranscriptome profiling as well as AS data of LUAD were retrospectively curated. Then, the network of the overall survival (OS)-relevant AS events with splicing factors was established. After screening OS-relevant AS events, a LASSO prognostic model was conducted and evaluated with ROC curves. A nomogram that integrated independent prognostic indicators was created. Immune response and immune cell infiltration were estimated with ESTIMATE, CIBERSORT, and ssGSEA algorithms. Drug sensitivity was inferred with pRRophetic package.ResultsIn total, 2415 OS-relevant AS events were identified across LUAD patients. The interaction network of splicing factors with OS-relevant AS events uncovered the underlying regulatory mechanisms of AS events in LUAD. Thereafter, a prognostic model containing 12 AS events was developed, which acted as a reliable and independent prognostic indicator following verification. A nomogram that constituted stage and risk score displayed great effectiveness in evaluating the survival likelihood. Moreover, the AS-based prognostic model was in relation to immune response and immune cell infiltration. Patients with a high-risk score displayed therapeutic superiority to cisplatin, erlotinib, gefitinib, and gemcitabine. Finally, three AS-relevant genes (CDKN2A, TTC39C, and PKIB) were identified as prognostic markers.ConclusionCollectively, our findings developed an AS event signature with powerful prognostic predictive efficacy in LUAD.
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