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Journal of Advanced Research Mar 2022The intestinal tract is a complicated ecosystem with dynamic homeostasis via interaction of intestine and microbiota. Inflammatory bowel disease (IBD) is chronic... (Review)
Review
BACKGROUND
The intestinal tract is a complicated ecosystem with dynamic homeostasis via interaction of intestine and microbiota. Inflammatory bowel disease (IBD) is chronic intestinal inflammation involving dysbiosis of intestinal microenvironment. Extracellular vesicles (EVs), as vital characteristics of cell-cell and cell-organism communication, contribute to homeostasis in intestine. Recently, EVs showed excellent potential for clinical applications in disease diagnoses and therapies.
AIM OF REVIEW
Our current review discusses the modulatory functions of EVs derived from different sources in intestine, especially their effects and applications in IBD clinical therapy. EV-mediated interaction systems between host intestine and microbiota were established to describe possible mechanisms of IBD pathogenesis and its cure.
KEY SCIENTIFIC CONCEPTS OF REVIEW
EVs are excellent vehicles for delivering molecules containing genetic information to recipient cells. Multiple pieces of evidence have illustrated that EVs participate the interaction between host and microbiota in intestinal microenvironment. In inflammatory intestine with dysbiosis of microbiota, EVs as regulators target promoting immune response and microbial reconstruction. EVs-based immunotherapy could be a promising therapeutic approach for the treatment of IBD in the near future.
Topics: Dysbiosis; Extracellular Vesicles; Humans; Inflammatory Bowel Diseases; Intestines; Microbiota
PubMed: 35499059
DOI: 10.1016/j.jare.2021.07.002 -
Cell Death and Differentiation Sep 2022Ferroptosis, a novel form of regulated cell death induced by iron-dependent lipid peroxidation, plays an essential role in the development and drug resistance of tumors....
Ferroptosis, a novel form of regulated cell death induced by iron-dependent lipid peroxidation, plays an essential role in the development and drug resistance of tumors. Long noncoding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to be involved in the regulation of cell cycle, proliferation, apoptosis, and migration of tumor cells. However, the function and molecular mechanism of NEAT1 in regulating ferroptosis in tumors remain unclear. Here, we found that ferroptosis inducers erastin and RSL3 increased NEAT1 expression by promoting the binding of p53 to the NEAT1 promoter. Induced NEAT1 promoted the expression of MIOX by competitively binding to miR-362-3p. MIOX increased ROS production and decreased the intracellular levels of NADPH and GSH, resulting in enhanced erastin- and RSL3-induced ferroptosis. Importantly, overexpression of NEAT1 increased the anti-tumor activity of erastin and RSL3 by enhancing ferroptosis both in vitro and in vivo. Collectively, these data suggest that NEAT1 plays a novel and indispensable role in ferroptosis by regulating miR-362-3p and MIOX. Considering the clinical findings that HCC patients are insensitive to chemotherapy and immunotherapy, ferroptosis induction may be a promising therapeutic strategy for HCC patients with high NEAT1 expression.
Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Ferroptosis; Humans; Inositol Oxygenase; Liver Neoplasms; MicroRNAs; RNA, Long Noncoding
PubMed: 35338333
DOI: 10.1038/s41418-022-00970-9 -
Molecular Cell Dec 2019Visualizing the location and dynamics of RNAs in live cells is key to understanding their function. Here, we identify two endonuclease-deficient, single-component...
Visualizing the location and dynamics of RNAs in live cells is key to understanding their function. Here, we identify two endonuclease-deficient, single-component programmable RNA-guided and RNA-targeting Cas13 RNases (dCas13s) that allow robust real-time imaging and tracking of RNAs in live cells, even when using single 20- to 27-nt-long guide RNAs. Compared to the aptamer-based MS2-MCP strategy, an optimized dCas13 system is user friendly, does not require genetic manipulation, and achieves comparable RNA-labeling efficiency. We demonstrate that the dCas13 system is capable of labeling NEAT1, SatIII, MUC4, and GCN4 RNAs and allows the study of paraspeckle-associated NEAT1 dynamics. Applying orthogonal dCas13 proteins or combining dCas13 and MS2-MCP allows dual-color imaging of RNAs in single cells. Further combination of dCas13 and dCas9 systems allows simultaneous visualization of genomic DNA and RNA transcripts in living cells.
Topics: CRISPR-Cas Systems; Cell Line, Tumor; Fluorescent Dyes; Humans; Molecular Imaging; Mucin-4; Protein Engineering; RNA; RNA, Guide, CRISPR-Cas Systems; RNA, Long Noncoding; Ribonucleases; Single Molecule Imaging; Staining and Labeling
PubMed: 31757757
DOI: 10.1016/j.molcel.2019.10.024 -
Ageing Research Reviews Apr 2023Neurodegenerative diseases are the most common causes of disability worldwide. Given their high prevalence, devastating symptoms, and lack of definitive diagnostic... (Review)
Review
Neurodegenerative diseases are the most common causes of disability worldwide. Given their high prevalence, devastating symptoms, and lack of definitive diagnostic tests, there is an urgent need to identify potential biomarkers and new therapeutic targets. Long non-coding RNAs (lncRNAs) have recently emerged as powerful regulatory molecules in neurodegenerative diseases. Among them, lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to be upregulated in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). However, whether this is part of a protective or harmful mechanism is still unclear. This review summarizes our current knowledge of the role of NEAT1 in neurodegenerative diseases and its association with the characteristic aggregation of misfolded proteins: amyloid-β and tau in AD, α-synuclein in PD, mutant huntingtin in HD, and TAR DNA-binding protein-43 fused in sarcoma/translocated in liposarcoma in ALS. The aim of this review is to stimulate further research on more precise and effective treatments for neurodegenerative diseases.
Topics: Humans; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Huntington Disease; Neurodegenerative Diseases; Parkinson Disease; RNA, Long Noncoding
PubMed: 36738893
DOI: 10.1016/j.arr.2023.101878 -
American Journal of Cancer Research 2021Liquid-liquid phase separation (LLPS) has emerged as a mechanism that has been used to explain the formation of known organelles (e.g. nucleoli, promyelocytic leukemia... (Review)
Review
Liquid-liquid phase separation (LLPS) has emerged as a mechanism that has been used to explain the formation of known organelles (e.g. nucleoli, promyelocytic leukemia nuclear bodies (PML NBs), etc) as well as other membraneless condensates (e.g. nucleosome arrays, DNA damage foci, X-chromosome inactivation (XCI) center, paraspeckles, stress granules, proteasomes, autophagosomes, etc). The formation of membraneless condensates could be triggered by proteins containing modular domains or intrinsically disordered regions (IDRs) and nucleic acids. Multiple biological processes including transcription, chromatin organization, X-chromosome inactivation (XCI), DNA damage, tumorigenesis, autophagy, etc have been shown to utilize the principle of LLPS to facilitate these processes. This review will summarize the principle and components of LLPS, and describe how LLPS regulate these numerous biological processes and disruption of LLPS would cause disease formation. The role of LLPS in regulating normal cellular physiology and contributing to tumorigenesis will be discussed.
PubMed: 34522448
DOI: No ID Found -
Cell Metabolism Dec 2021Accelerated glycolysis is the main metabolic change observed in cancer, but the underlying molecular mechanisms and their role in cancer progression remain poorly...
Accelerated glycolysis is the main metabolic change observed in cancer, but the underlying molecular mechanisms and their role in cancer progression remain poorly understood. Here, we show that the deletion of the long noncoding RNA (lncRNA) Neat1 in MMTV-PyVT mice profoundly impairs tumor initiation, growth, and metastasis, specifically switching off the penultimate step of glycolysis. Mechanistically, NEAT1 directly binds and forms a scaffold bridge for the assembly of PGK1/PGAM1/ENO1 complexes and thereby promotes substrate channeling for high and efficient glycolysis. Notably, NEAT1 is upregulated in cancer patients and correlates with high levels of these complexes, and genetic and pharmacological blockade of penultimate glycolysis ablates NEAT1-dependent tumorigenesis. Finally, we demonstrate that Pinin mediates glucose-stimulated nuclear export of NEAT1, through which it exerts isoform-specific and paraspeckle-independent functions. These findings establish a direct role for NEAT1 in regulating tumor metabolism, provide new insights into the Warburg effect, and identify potential targets for therapy.
Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Glycolysis; Humans; Mice; MicroRNAs; RNA, Long Noncoding
PubMed: 34879239
DOI: 10.1016/j.cmet.2021.11.011 -
Advanced Science (Weinheim,... Jun 2021Molecular heterogeneity of hepatobiliary tumor including intertumoral and intratumoral disparity always leads to drug resistance. Here, seven hepatobiliary tumor...
Molecular heterogeneity of hepatobiliary tumor including intertumoral and intratumoral disparity always leads to drug resistance. Here, seven hepatobiliary tumor organoids are generated to explore heterogeneity and evolution via single-cell RNA sequencing. HCC272 with high status of epithelia-mesenchymal transition proves broad-spectrum drug resistance. By examining the expression pattern of cancer stem cells markers (e.g., PROM1, CD44, and EPCAM), it is found that CD44 positive population may render drug resistance in HCC272. UMAP and pseudo-time analysis identify the intratumoral heterogeneity and distinct evolutionary trajectories, of which catenin beta-1 (CTNNB1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and nuclear paraspeckle assembly transcript 1 (NEAT1) advantage expression clusters are commonly shared across hepatobiliary organoids. CellphoneDB analysis further implies that metabolism advantage organoids with enrichment of hypoxia signal upregulate NEAT1 expression in CD44 subgroup and mediate drug resistance that relies on Jak-STAT pathway. Moreover, metabolism advantage clusters shared in several organoids have similar characteristic genes (GAPDH, NDRG1 (N-Myc downstream regulated 1), ALDOA, and CA9). The combination of GAPDH and NDRG1 is an independent risk factor and predictor for patient survival. This study delineates heterogeneity of hepatobiliary tumor organoids and proposes that the collaboration of intratumoral heterogenic subpopulations renders malignant phenotypes and drug resistance.
Topics: Antigens, Neoplasm; Carbonic Anhydrase IX; Cell Cycle Proteins; Digestive System Diseases; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Fructose-Bisphosphate Aldolase; Gastrointestinal Neoplasms; Gene Expression Regulation, Neoplastic; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Humans; Hyaluronan Receptors; Intracellular Signaling Peptides and Proteins; Janus Kinases; Neoplastic Stem Cells; Organoids; RNA, Long Noncoding; RNA-Seq; STAT Transcription Factors; Single-Cell Analysis; Transcriptome; beta Catenin
PubMed: 34105295
DOI: 10.1002/advs.202003897 -
Theranostics 2022Hepatocellular Carcinoma (HCC) is a major form of liver cancer and a leading cause of cancer-related death worldwide. New insights into HCC pathobiology and mechanism...
Hepatocellular Carcinoma (HCC) is a major form of liver cancer and a leading cause of cancer-related death worldwide. New insights into HCC pathobiology and mechanism of drug actions are urgently needed to improve patient outcomes. HCC undergoes metabolic reprogramming of glucose metabolism from respiration to aerobic glycolysis, a phenomenon known as the 'Warburg Effect' that supports rapid cancer cell growth, survival, and invasion. mTOR is known to promote Warburg Effect, but the underlying mechanism(s) remains poorly defined. The aim of this study is to understand the mechanism(s) and significance of mTOR regulation of aerobic glycolysis in HCC. We profiled mTORC1-dependent long non-coding RNAs (lncRNAs) by RNA-seq of HCC cells treated with rapamycin. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were used to explore the transcriptional regulation of by mTORC1. [U-C]-glucose labeling and metabolomic analysis, extracellular acidification Rate (ECAR) by Seahorse XF Analyzer, and glucose uptake assay were used to investigate the role of mTOR-NEAT1-NONO signaling in the regulation of aerobic glycolysis. RNA immunoprecipitation (RIP) and NONO-binding motif scanning were performed to identify the regulatory mechanism of pre-mRNA splicing by mTOR-NEAT1. Myristoylated AKT1 (mAKT1)/NRAS-driven HCC model developed by hydrodynamic transfection (HDT) was employed to explore the significance of mTOR-NEAT1 signaling in HCC tumorigenesis and mTOR-targeted therapy. mTOR regulates lncRNA transcriptome in HCC and that NEAT1 is a major mTOR transcriptional target. Interestingly, although both NEAT1_1 and NEAT1_2 are down-regulated in HCC, only NEAT1_2 is significantly correlated with poor overall survival of HCC patients. NEAT1_2 is the organizer of nuclear paraspeckles that sequester the RNA-binding proteins NONO and SFPQ. We show that upon oncogenic activation, mTORC1 suppresses NEAT1_2 expression and paraspeckle biogenesis, liberating NONO/SFPQ, which in turn, binds to U5 within the spliceosome, stimulating mRNA splicing and expression of key glycolytic enzymes. This series of actions lead to enhanced glucose transport, aerobic glycolytic flux, lactate production, and HCC growth both and . Furthermore, the paraspeckle-mediated mechanism is important for the anticancer action of US FDA-approved drugs rapamycin/temsirolimus. These findings reveal a molecular mechanism by which mTOR promotes the 'Warburg Effect', which is important for the metabolism and development of HCC, and anticancer response of mTOR-targeted therapy.
Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Glucose; Glycolysis; Humans; Liver Neoplasms; Mechanistic Target of Rapamycin Complex 1; Paraspeckles; RNA, Long Noncoding; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 35547764
DOI: 10.7150/thno.72581 -
Cold Spring Harbor Perspectives in... Jul 2010Paraspeckles are a relatively new class of subnuclear bodies found in the interchromatin space of mammalian cells. They are RNA-protein structures formed by the... (Review)
Review
Paraspeckles are a relatively new class of subnuclear bodies found in the interchromatin space of mammalian cells. They are RNA-protein structures formed by the interaction between a long nonprotein-coding RNA species, NEAT1/Men epsilon/beta, and members of the DBHS (Drosophila Behavior Human Splicing) family of proteins: P54NRB/NONO, PSPC1, and PSF/SFPQ. Paraspeckles are critical to the control of gene expression through the nuclear retention of RNA containing double-stranded RNA regions that have been subject to adenosine-to-inosine editing. Through this mechanism paraspeckles and their components may ultimately have a role in controlling gene expression during many cellular processes including differentiation, viral infection, and stress responses.
Topics: Cell Nucleus; Humans; Microscopy, Fluorescence; Subcellular Fractions
PubMed: 20573717
DOI: 10.1101/cshperspect.a000687 -
Non-coding RNA Oct 2020Non-coding RNA were previously thought to be biologically useless molecules arising from simple transcriptional noise. These are now known to be an integral part of... (Review)
Review
Non-coding RNA were previously thought to be biologically useless molecules arising from simple transcriptional noise. These are now known to be an integral part of cellular biology and pathology. The wide range of RNA molecules have a diverse range of structures, functions, and mechanisms of action. However, structural long non-coding RNAs (lncRNAs) are a particular class of ncRNA that are proving themselves more and more important in cellular biology, as the exact structures that such RNAs form and stabilise become more understood. Nuclear Enriched Abundant Transcript 1 (NEAT1) is a specific structural RNA emerging as a critical component in the progress and development of cancer. NEAT1 forms part of multiple biological pathways, acting through a diverse group of mechanisms. The most important of these is the formation of the paraspeckle, through which it can influence the stability of a tumour to develop resistance to drugs. This review will thus cover the range of effects by which NEAT1 interacts with cancer progression in order to describe the various roles of NEAT1 in chemoresistance, as well as to identify drug targets that protein research alone could not provide.
PubMed: 33143162
DOI: 10.3390/ncrna6040043