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Journal of Cell Communication and... Sep 2023Gynecologic cancers are a worldwide problem among women. Recently, molecular targeted therapy opened up an avenue for cancer diagnosis and treatment. Long non-coding... (Review)
Review
Gynecologic cancers are a worldwide problem among women. Recently, molecular targeted therapy opened up an avenue for cancer diagnosis and treatment. Long non-coding RNAs (lncRNAs) are RNA molecules (> 200 nt) that are not translated into protein, and interact with DNA, RNA, and proteins. LncRNAs were found to play pivotal roles in cancer tumorigenesis and progression. Nuclear paraspeckle assembly transcript 1 (NEAT1) is a lncRNA that mediates cell proliferation, migration, and EMT in gynecologic cancers by targeting several miRNAs/mRNA axes. Therefore, NEAT1 may function as a potent biomarker for the prediction and treatment of breast, ovarian, cervical, and endometrial cancers. In this narrative review, we summarized various NEAT1-related signaling pathways that are critical in gynecologic cancers. Long non-coding RNA (lncRNA) by targeting various signaling pathways involved in its target genes can regulate the occurrence of gynecologic cancers.
PubMed: 37310654
DOI: 10.1007/s12079-023-00746-x -
Nature Communications Jun 2023Long noncoding RNAs (lncRNAs) are linked to cancer via pathogenic changes in their expression levels. Yet, it remains unclear whether lncRNAs can also impact tumour cell...
Long noncoding RNAs (lncRNAs) are linked to cancer via pathogenic changes in their expression levels. Yet, it remains unclear whether lncRNAs can also impact tumour cell fitness via function-altering somatic "driver" mutations. To search for such driver-lncRNAs, we here perform a genome-wide analysis of fitness-altering single nucleotide variants (SNVs) across a cohort of 2583 primary and 3527 metastatic tumours. The resulting 54 mutated and positively-selected lncRNAs are significantly enriched for previously-reported cancer genes and a range of clinical and genomic features. A number of these lncRNAs promote tumour cell proliferation when overexpressed in in vitro models. Our results also highlight a dense SNV hotspot in the widely-studied NEAT1 oncogene. To directly evaluate the functional significance of NEAT1 SNVs, we use in cellulo mutagenesis to introduce tumour-like mutations in the gene and observe a significant and reproducible increase in cell fitness, both in vitro and in a mouse model. Mechanistic studies reveal that SNVs remodel the NEAT1 ribonucleoprotein and boost subnuclear paraspeckles. In summary, this work demonstrates the utility of driver analysis for mapping cancer-promoting lncRNAs, and provides experimental evidence that somatic mutations can act through lncRNAs to enhance pathological cancer cell fitness.
Topics: Animals; Mice; RNA, Long Noncoding; Neoplasms; Mutation; Oncogenes; Genomics
PubMed: 37291246
DOI: 10.1038/s41467-023-39160-7 -
Immunity, Inflammation and Disease May 2023Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) have been reported to play regulatory roles in ulcerative colitis (UC). In this study, we aimed to determine the...
BACKGROUND
Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) have been reported to play regulatory roles in ulcerative colitis (UC). In this study, we aimed to determine the specific roles and action mechanism of the nuclear paraspeckle assembly transcript 1 (NEAT1) in UC.
METHODS
Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to determine the lncRNA NEAT1 and miR-493-5p expression levels in patients with UC and healthy volunteers. We determine the forecast linkage points of NEAT1 and miR-493-5p using Starbase and those of miR-493-5p and Rab27A using TargetScan, and further verified them using a double luciferase gene reporter kit. RT-qPCR and Western blot analysis were used to determine the lncRNA NEAT1, miR-493-5p, and Rab27A expression levels in lipopolysaccharide (LPS)-induced Caco-2 cells. Flow cytometry and cell counting kit-8 were used to assess Caco-2 cell viability. Tumor necrosis factor-α, interleukin (IL)-6, IL-8, and IL-1β levels were determined via an enzyme-linked immunosorbent assay.
RESULTS
Expression levels of NEAT1 were upregulated and those of miR-493-5p were downregualted in 10 ng/mL LPS-treated Caco-2 cells and patients with UC. Dual-luciferase gene reporter assay revealed that miR-493-5p is linked to NEAT1, and Rab27A is a downstream target of miR-493-5p. Overexpression of miR-493-5p inhibited the apoptosis and inflammation in LPS-treated Caco-2 cells. Moreover, downregulation of lncRNA NEAT1 expression also inhibited the apoptosis and inflammation in LPS-treated Caco-2 cells, which was reversed by Rab27A plasmid cotransfection.
CONCLUSION
Our results revealed that NEAT1 participates in UC progression by inhibiting miR-493-5p expression.
Topics: Humans; Caco-2 Cells; Cell Proliferation; Colitis, Ulcerative; Inflammation; Lipopolysaccharides; MicroRNAs; rab27 GTP-Binding Proteins; RNA, Long Noncoding
PubMed: 37249278
DOI: 10.1002/iid3.814 -
Genes May 2023G-quadruplexes (G4s) have long been implicated in the regulation of chromatin packaging and gene expression. These processes require or are accelerated by the separation... (Review)
Review
G-quadruplexes (G4s) have long been implicated in the regulation of chromatin packaging and gene expression. These processes require or are accelerated by the separation of related proteins into liquid condensates on DNA/RNA matrices. While cytoplasmic G4s are acknowledged scaffolds of potentially pathogenic condensates, the possible contribution of G4s to phase transitions in the nucleus has only recently come to light. In this review, we summarize the growing evidence for the G4-dependent assembly of biomolecular condensates at telomeres and transcription initiation sites, as well as nucleoli, speckles, and paraspeckles. The limitations of the underlying assays and the remaining open questions are outlined. We also discuss the molecular basis for the apparent permissive role of G4s in the in vitro condensate assembly based on the interactome data. To highlight the prospects and risks of G4-targeting therapies with respect to the phase transitions, we also touch upon the reported effects of G4-stabilizing small molecules on nuclear biomolecular condensates.
Topics: G-Quadruplexes; Biomolecular Condensates; Cell Nucleus; RNA; Proteins
PubMed: 37239436
DOI: 10.3390/genes14051076 -
Human Pathology Aug 2023Prostate cancer (PCa) remains the most commonly diagnosed cancer in men worldwide and is still the second leading cause of cancer-related death. One major cause of PCa...
Prostate cancer (PCa) remains the most commonly diagnosed cancer in men worldwide and is still the second leading cause of cancer-related death. One major cause of PCa development is epigenetic aberration, including histone modification. We have previously demonstrated that Lysine Demethylase 5C (KDM5C) plays an essential role in the development of PCa and drives PCa progression by promoting epithelial-mesenchymal transition. Epigenetic regulators often work in concert, for example, to regulate transcription. We identified Paraspeckle Component 1 (PSPC1) as an interacting protein of KDM5C, suggesting that these proteins might function together in PCa. Here, we systematically investigate the expression patterns of KDM5C and PSPC1 in 2 independent prostate cohorts (432 and 205 prostate tumors in total for PSPC1 and KDM5C, respectively) by immunohistochemistry. We demonstrate that the expression of PSPC1 correlates with that of KDM5C. In addition, PSPC1 is up-regulated in primary and metastatic PCa. Elevated PSPC1 expression correlates with a higher-grade group and an advanced T-stage. Patients with high PSPC1 expression have a worse biochemical recurrence-free survival. In addition, PSPC1 expression is an independent prognostic parameter. Our data indicate that KDM5C and PSPC1 are involved in PCa progression, and therapeutic inhibition of KDM5C and PSPC1 by selective compounds might be a promising approach for the treatment of PCa.
Topics: Male; Humans; Prostatic Neoplasms; Prostate; Epithelial-Mesenchymal Transition; RNA-Binding Proteins; Histone Demethylases
PubMed: 37209920
DOI: 10.1016/j.humpath.2023.05.007 -
Experimental Cell Research Jun 2023Nuclear speckles are subcellular structures originally characterized by punctate immunofluorescence staining of the monoclonal antibody SC35, which recognizes an epitope... (Review)
Review
Nuclear speckles are subcellular structures originally characterized by punctate immunofluorescence staining of the monoclonal antibody SC35, which recognizes an epitope on SRRM2 (serine/arginine repetitive matrix protein 2) and Sfrs2, a member of the SR (serine/arginine-rich) family of splicing factors. Galectin-3 co-localizes with SC35 in nuclear speckles, which represent one group of nuclear bodies that include the nucleolus, Cajal bodies and gems, paraspeckles, etc. Although they appear to have well-delineated physical boundaries, these nuclear bodies are not membrane-bound structures but represent macromolecular assemblies arising from a phenomenon called liquid-liquid phase separation. There has been much recent interest in liquid phase condensation as a newly recognized mechanism by which a cell can organize and compartmentalize subcellular structures with distinct composition. The punctate/speckled staining of galectin-3 with SC3 demonstrates their co-localization in a phase-separated body in vivo, under conditions endogenous to the cell. The purpose of the present review is to summarize the studies that document three key features of galectin-3 for its localization in liquid phase condensates: (a) an intrinsically disordered domain; (b) oligomer formation for multivalent binding; and (c) association with RNA and ribonucleoprotein complexes.
Topics: Galectin 3; Nuclear Speckles; Cell Nucleolus; Ribonucleoproteins; Arginine
PubMed: 37003559
DOI: 10.1016/j.yexcr.2023.113571 -
Cell Death Discovery Mar 2023There is growing evidence that long non-coding RNAs (lncRNAs) are significant contributors to the epigenetic mechanisms implicated in the emergence, progression and...
There is growing evidence that long non-coding RNAs (lncRNAs) are significant contributors to the epigenetic mechanisms implicated in the emergence, progression and metastasis of the colorectal cancer (CRC), but many remain underexplored. A novel lncRNA LOC105369504, was identified to be a potential functional lncRNA by microarray analysis. In CRC, the expression of LOC105369504 was markedly decreased and resulted in distinct variations in proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) in vivo and in vitro. This study showed that LOC105369504 bound to the protein of paraspeckles compound 1 (PSPC1) directly and regulated its stability using the ubiquitin-proteasome pathway in CRC cells. The suppression of CRC by LOC105369504 could be reversed through PSPC1 overexpression.This study showed that in CRC, LOC105369504 was under-regulated and as a novel lncRNA, LOC105369504 exerted tumor suppressive activity to suppress the proliferation together with metastasis in CRC cells through the regulation of PSPC1. These results offer new perspectives on the lncRNA effect on the progression of CRC.
PubMed: 36894530
DOI: 10.1038/s41420-023-01384-3 -
Current Issues in Molecular Biology Jan 2023This study investigated the effects of a long noncoding RNA, nuclear paraspeckle assembly transcript 1 (NEAT1) variant 1 (NEAT1v1) on drug resistance in liver cancer...
This study investigated the effects of a long noncoding RNA, nuclear paraspeckle assembly transcript 1 (NEAT1) variant 1 (NEAT1v1) on drug resistance in liver cancer cell lines. NEAT1 knockdown activated mitogen-activated protein kinase (MAPK) signaling pathways, including MAPK kinase (MEK)/extracellular signal-regulated kinase (ERK), but suppressed AKT. Moreover, NEAT1 knockdown sensitized liver cancer cells to sorafenib and lenvatinib, both clinically used for treating hepatocellular carcinoma, whereas it conferred resistance to an AKT-targeted drug, capivasertib. NEAT1v1 overexpression suppressed MEK/ERK and activated AKT, resulting in resistance to sorafenib and lenvatinib and sensitization to capivasertib. Superoxide dismutase 2 (SOD2) knockdown reverted the effects of NEAT1v1 overexpression on the sensitivity to the molecular-targeted drugs. Although NEAT1 or SOD2 knockdown enhanced endoplasmic reticulum (ER) stress, concomitant with the suppression of AKT, taurodeoxycholate, an ER stress suppressor, did not restore AKT activity. Although further in vivo and clinical studies are needed, these results suggested that NEAT1v1 switches the growth modality of liver cancer cell lines from MEK/ERK-dependent to AKT-dependent mode via SOD2 and regulates sensitivity to the molecular-targeted drugs independent of ER stress.
PubMed: 36826016
DOI: 10.3390/cimb45020071 -
Molecular Therapy : the Journal of the... Jun 2023The human genome is pervasively transcribed, producing a majority of short and long noncoding RNAs (lncRNAs) that can influence cellular programs through a variety of... (Review)
Review
The human genome is pervasively transcribed, producing a majority of short and long noncoding RNAs (lncRNAs) that can influence cellular programs through a variety of transcriptional and post-transcriptional regulatory mechanisms. The brain houses the richest repertoire of long noncoding transcripts, which function at every stage during central nervous system development and homeostasis. An example of functionally relevant lncRNAs is species involved in spatiotemporal organization of gene expression in different brain regions, which play roles at the nuclear level and in transport, translation, and decay of other transcripts in specific neuronal sites. Research in the field has enabled identification of the contributions of specific lncRNAs to certain brain diseases, including Alzheimer's disease, Parkinson's disease, cancer, and neurodevelopmental disorders, resulting in notions of potential therapeutic strategies that target these RNAs to recover the normal phenotype. Here, we summarize the latest mechanistic findings associated with lncRNAs in the brain, focusing on their dysregulation in neurodevelopmental or neurodegenerative disorders, their use as biomarkers for central nervous system (CNS) diseases in vitro and in vivo, and their potential utility for therapeutic strategies.
Topics: Humans; Brain; RNA, Long Noncoding; Neurogenesis; Gene Expression Regulation, Developmental; Neurodevelopmental Disorders; Neurodegenerative Diseases
PubMed: 36793211
DOI: 10.1016/j.ymthe.2023.02.008 -
Nature Communications Feb 2023Myofibroblasts cause tissue fibrosis by producing extracellular matrix proteins, such as collagens. Humoral factors like TGF-β, and matrix stiffness are important for...
Myofibroblasts cause tissue fibrosis by producing extracellular matrix proteins, such as collagens. Humoral factors like TGF-β, and matrix stiffness are important for collagen production by myofibroblasts. However, the molecular mechanisms regulating their ability to produce collagen remain poorly characterised. Here, we show that vestigial-like family member 3 (VGLL3) is specifically expressed in myofibroblasts from mouse and human fibrotic hearts and promotes collagen production. Further, substrate stiffness triggers VGLL3 translocation into the nucleus through the integrin β1-Rho-actin pathway. In the nucleus, VGLL3 undergoes liquid-liquid phase separation via its low-complexity domain and is incorporated into non-paraspeckle NONO condensates containing EWS RNA-binding protein 1 (EWSR1). VGLL3 binds EWSR1 and suppresses miR-29b, which targets collagen mRNA. Consistently, cardiac fibrosis after myocardial infarction is significantly attenuated in Vgll3-deficient mice, with increased miR-29b expression. Overall, our results reveal an unrecognised VGLL3-mediated pathway that controls myofibroblasts' collagen production, representing a novel therapeutic target for tissue fibrosis.
Topics: Humans; Mice; Animals; Myocardium; Transforming Growth Factor beta1; Fibrosis; Collagen; Myofibroblasts; Transcription Factors; MicroRNAs; Fibroblasts; Cells, Cultured
PubMed: 36754961
DOI: 10.1038/s41467-023-36189-6