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At least 1,009 records · Page 56Linked to original sources
PubMed2003

Post-transcriptional gene silencing in plants by RNA.

RNA silencing, which is termed post-transcriptional gene silencing in plants, is an RNA degradation process through sequence-specific nucleotide interactions induced by double-stranded RNA. In plants, RNA silencing not only serves as a component of the defense mechanism, but also participates in the regulation of endogenous gene expression in a variety of developmental processes. This review elaborates the current progress on the understanding of the molecular basis of RNA silencing including a mechanistic link between the regulation of microRNA and RNA silencing. The practical use of RNA silencing as a reverse genetics approach in plant functional genomics is also discussed.

Gene Silencing↗
PubMed2026

miR-191 affects skeletal muscle differentiation by regulating Wwp1 in mouse myoblasts.

Skeletal muscle atrophy is a key complication of various diseases, such as chronic obstructive pulmonary disease (COPD) and cancer. The mechanisms by which these diseases affect skeletal muscle metabolism need to be deeply explored. By analyzing the miRNA expression profiles in the plasma of patients with COPD, we found that miR-191 expression was significantly altered and it may influence skeletal muscle metabolism by regulating ubiquitination and the mTOR pathway. Using a mouse model of skeletal muscle injury induced by cardiotoxin, we found that miR-191 and Wwp1 showed a dynamic negative correlation in injury repair. Transfection with miR-191 mimics significantly inhibited the expression of myogenic regulatory factor Myog and differentiation markers Myh1/7/8, while downregulating key genes in the mTOR pathway. Molecular mechanism studies showed that miR-191 could directly act on the 3' untranslated region of the Wwp1 gene to inhibit its expression. This study reveals the important role of the miR-191/Wwp1 axis in skeletal muscle differentiation and provides a novel theoretical basis for research on muscle atrophy induced by COPD, cancer cachexia, and other diseases.

Animals↗
PubMed2026

Transcriptome changes in circulating immune cells of critical COVID-19 patients predict a specific metabolic and epigenetic imprint.

BACKGROUND: The progression to critical COVID-19 arises predominantly from a dysregulated host immune response although the underlying regulatory mechanisms still remain partially elusive. This limits a prompt prediction of the disease progression, reduces the therapeutic options and restrains our understanding of “long COVID”. METHODS: Here, we analyzed the transcriptome of peripheral blood mononuclear cells (PBMCs) collected from COVID-19 patients experiencing different degrees of the disease (mild and critical), and control patients enrolled in the clinical trial COntAGIouS as well as independent bulk RNA-seq, single-cell RNA-seq and proteomic datasets. RESULTS: In critical COVID-19 patients, the integrative analysis of transcriptomic data revealed an altered regulatory network involving microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and coding genes that control mRNA translation-related genes, epigenetics, and metabolism. In parallel, we observed an upregulation of tRNA aminoacylation genes in critical COVID-19 patients by the analysis of either bulk or single-cell RNA-seq data from publicly available independent cohorts. Additionally, we found increased expression of coding genes enriched for the cognate amino acids (glycine, alanine, isoleucine and tyrosine), all related to protein localization, post-translational modifications, and cell metabolism in our cohort. Similar alterations in amino acid frequency were found in an independent proteomic dataset. CONCLUSIONS: Collectively, our findings indicate a broad perturbation of the gene expression landscape that characterizes the aberrant host immune response in critical COVID-19 patients and is potentially coordinated by miRNA and tRNA metabolism alterations. TRIAL REGISTRATION: COntAGIouS, NCT04327570. Registered 26 March 2020, https://clinicaltrials.gov/ct2/show/NCT04327570 .

Female↗
PubMed2025

Proteomic profiling identifies miR-423-5p as a modulator of oncogenic metabolism in HCC.

BACKGROUND: Hepatocellular carcinoma (HCC) remains a significant clinical challenge due to limited diagnostic and therapeutic options. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), play key roles in cancer biology. Our previous findings showed that miR-423-5p enhances anti-cancer effects on HCC patients treated with sorafenib by promoting autophagy. Here, we investigated the molecular mechanisms underlying miR-423-5p function through a comprehensive proteomic approach. METHODS: We generated an HCC cell line stably overexpressing miR-423-5p via lentiviral transduction. Total proteins were extracted from SNU-387 cells, enzymatically digested into peptides, and subsequently analysed by liquid chromatography-tandem mass spectrometry (LC-MS/M). Raw spectral data were processed and quantified using MaxQuant. Differentially expressed proteins (DEPs) were defined based on fold-change (|log2FC| &#x2265; 1) and false discovery rate (FDR < 0.05). The full proteomic dataset is available via the ProteomeXchange repository (identifier: PXD064869). Functional enrichment analysis of DEPs were performed using DAVID and Reactome. To assess clinical relevance, predicted and validated miR-423-5p targets were integrated with The Cancer Genome Atlas (TCGA) Liver Hepatocellular Carcinoma (LIHC) dataset using GEPIA platform. Survival analyses were performed using the Kaplan-Meier method. RESULTS: Proteomic profiling identified 698 DEPs in miR-423-5p-overexpressing cells compared to controls with significant enrichment in metabolic pathways, related to purine/pyrimidine metabolism and gluconeogenesis. Integration with bioinformatic predictions and miRTarBase validation identified 43 DEPs as potential direct targets of miR-423-5p. Among these, seven proteins (ACACA, ANKRD52, DVL3, MCM5, MCM7, RRM2, SPNS1, and SRM) were significantly associated with patient prognosis in the TCGA-LIHC cohort. These targets were downregulated in miR-423-5p-overexpressing cells but upregulated in advanced-stage HCC tissues, suggesting a potential role for miR-423-5p in the regulation of HCC pathogenesis. Stage-specific expression analysis showed increased levels from stage I to III, followed by a decline at stage IV. Notably, we experimentally confirmed miR-423-5p-mediated suppression of MCM7, DVL3, IMPDH1, and SRM (SPEE), supporting their functional involvement in HCC progression. CONCLUSION: Overall, our findings support a tumour-suppressive role for miR-423-5p in HCC, mediated by modulation of metabolic pathways and suppression of oncogenic proteins. These results suggest that miR-423-5p and its downstream effectors may serve as promising biomarkers and potential therapeutic targets in HCC. HIGHLIGHTS: miR-423-5p acts as a tumor suppressor in HCC by targeting key nodes of pro-tumorigenic signalling. miR-423-5p significantly altered metabolic pathways, including purine/pyrimidine metabolism and gluconeogenesis. Seven miR-423-5p targets correlate with poor prognosis in TCGA-LIHC patients and are downregulated in miR-423-5p overexpressing HCC cells. miR-423-5p over-expression induces a significant downregulation of MCM7, DVL3, IMPDH1, SPEE in HCC cell models. miR-423-5p limits tumor metabolic plasticity, suggesting therapeutic potential.

MicroRNAs↗
PubMed2004

The plasmodesmatal transport pathway for homeotic proteins, silencing signals and viruses.

Non-cell-autonomous signals in the form of microRNAs and transcription factors could have important developmental functions. Plasmodesmata (PD) form a cytoplasmic network throughout the plant body and provide the means of symplasmic cell-to-cell transport in plants. Homeodomain transcription factors, small RNA molecules and viral genomic information move selectively to adjacent cells via PD microchannels. Tissue-specific expression studies of non-cell-autonomous transcription factors and RNA molecules have confirmed that their intercellular transport is a highly regulated process, which depends on the tissue, developmental stage and nature of the transported macromolecule. We have known for some time that gene-silencing signals spread both locally from cell to cell and across long distances following the source to sink transition. Recent work has provided evidence that small single-stranded silencing-induced RNAs and microRNA molecules are present in the phloem transport system of different plant species. Further, recent evidence has confirmed that the transport of silencing RNA via PD is a regulated and active process, and that an amplification-relay mechanism is in place for the long-distance spread of silencing signals.

Animals↗
PubMed2026

Diagnostic and Predictive Value of Circulating and Exosomal microRNAs in Ferroptosis-Associated Neurological Conditions: A Systematic Review and Meta-analysis.

Circulating microRNAs (miRNAs) have emerged as potential non-invasive markers for intracranial pathology, yet their diagnostic accuracy and relationship with ferroptosis-mediated neuronal damage remain poorly defined. The primary objective of this study was to evaluate the diagnostic and predictive potential of circulating and exosomal miRNAs across ferroptosis-associated neurological conditions and to explore their associations with ferroptosis-related pathways. Following PRISMA-DTA guidelines, a systematic literature search was conducted across PubMed, Scopus, Cochrane, and ScienceDirect, identifying 205 records. After screening for human clinical cohort validation, 7 studies were included in the qualitative synthesis and 5 in the quantitative meta-analysis. Pooled Area-under-the-Curve (AUC) was calculated using a random-effects inverse-variance model, while prognostic correlation coefficients (r) were synthesized using Fisher's Z-transformation. Methodological quality was assessed via QUADAS-2. Analysis of 7 clinical cohorts provided heterogeneous evidence on the diagnostic and prognostic potential of miRNAs. Random-effects pooling of the two eligible diagnostic AUC estimates yielded an exploratory pooled AUC of 0.87 (95% CI, 0.79-0.94; I2&#x2009;.90%). Prognostic synthesis of Group 2 identified an exploratory association between miRNA levels and clinical severity scales (exploratory pooled correlation coefficient of 0.67 (95% CI: 0.56-0.76; I2&#x2009;.714.4%). Selected miRNAs were mapped to ferroptosis-associated regulators, including SLC7A11, ABCB8, and SLC40A1. Exosomal miRNAs hold potential to indicate disease-associated molecular information, although comparative clinical evidence remains yet to be explored. Circulating and exosomal miRNAs show promising diagnostic and prognostic potential across selected neurological conditions. These findings highlight a potential mechanistic association between miRNA expression and ferroptosis-mediated neuronal injury.

Humans↗
PubMed2006

Identification and characterization of lin-28 homolog B (LIN28B) in human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Several studies have identified signature gene sets that may be useful as potential diagnostic tools by global microarray analysis. Here we report the cloning and characterization of a novel gene, lin-28 homolog B (LIN28B), which is overexpressed in hepatocellular carcinoma. The heterochronic gene lin-28 is a key regulator of developmental timing in the nematode Caenorhabditis elegans. Similar with lin-28 proteins, LIN28B conserves a cold shock domain and a pair of CCHC zinc finger domains. Phylogenetic analysis suggests that they might arise as a result of duplication from an ancestral gene. Overexpression of LIN28B was noted in most HCC cell lines and clinical samples. By western blot analysis using a polyclonal antibody against LIN28B, a short LIN28B isoform was also identified in non-tumor liver tissue and fetal liver. Although predominantly localized in the cytoplasm, we found that LIN28B protein shows cell cycle-dependent nuclear translocation in Huh7 cells. Induced expression of exogenous LIN28B in a tet-off cell line promoted cancer cell proliferation. Interestingly, the segment of the unusually long 3'UTR of LIN28B contains complementary sites to let-7 microRNA of mammals. And our studies provided indirect evidence that LIN28B is a possibly natural target for let-7 mediated regulation. These findings strongly implicate a critical role of LIN28B during development and tumorigenesis and suggest a possible novel mechanism.

3' Untranslated Regions↗
PubMedDate not supplied

[Genome-wide lentivector-based pooled shRNA library optimization].

We have optimized lentiviral vector constructs and cassettes for expression of short hairpin RNAs (shRNAs) in order to create genome-wide library capable of inhibition of full variety of human mRNAs. The vector optimization has resulted in 15-20-fold improvement in virus stock titers. We found that in the context of lentiviral vector the most effective structure for the shRNA is simple hairpin with 21 nucleotide stem. The shRNA-expressing lentiviral constructs contain choice of puro(R), copGFP or H-2K(k) selective markers. The efficiency of the optimized library was evaluated in experiments on screening of shRNAs that reactivate oncosuppressor p53 in HeLa cells. The cells contained reporter construct with p53-dependent expression of a fluorescent protein, which allows cytofluorimetric isolation of cell population with reactivated p53.

Gene Expression Regulation↗
PubMed2006

Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways.

RNA interference (RNAi) is a universal and evolutionarily conserved phenomenon of post-transcriptional gene silencing by means of sequence-specific mRNA degradation, triggered by small double-stranded RNAs. Because this mechanism can be efficiently induced in vivo by expressing target-complementary short hairpin RNA (shRNA) from non-viral and viral vectors, RNAi is attractive for functional genomics and human therapeutics. Here we systematically investigate the long-term effects of sustained high-level shRNA expression in livers of adult mice. Robust shRNA expression in all the hepatocytes after intravenous infusion was achieved with an optimized shRNA delivery vector based on duplex-DNA-containing adeno-associated virus type 8 (AAV8). An evaluation of 49 distinct AAV/shRNA vectors, unique in length and sequence and directed against six targets, showed that 36 resulted in dose-dependent liver injury, with 23 ultimately causing death. Morbidity was associated with the downregulation of liver-derived microRNAs (miRNAs), indicating possible competition of the latter with shRNAs for limiting cellular factors required for the processing of various small RNAs. In vitro and in vivo shRNA transfection studies implied that one such factor, shared by the shRNA/miRNA pathways and readily saturated, is the nuclear karyopherin exportin-5. Our findings have fundamental consequences for future RNAi-based strategies in animals and humans, because controlling intracellular shRNA expression levels will be imperative. However, the risk of oversaturating endogenous small RNA pathways can be minimized by optimizing shRNA dose and sequence, as exemplified here by our report of persistent and therapeutic RNAi against human hepatitis B virus in vivo.

Animals↗
PubMed2006

A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes.

The known classes of genes that function as tumor suppressors and oncogenes have recently been expanded to include the microRNA (miRNA) family of regulatory molecules. miRNAs negatively regulate the stability and translation of target messenger RNAs (mRNA) and have been implicated in diverse processes such as cellular differentiation, cell-cycle control and apoptosis. Examination of tumor-specific miRNA expression profiles has revealed widespread dysregulation of these molecules in diverse cancers. Although studies addressing their role in cancer pathogenesis are at an early stage, it is apparent that loss- or gain-of-function of specific miRNAs contributes to cellular transformation and tumorigenesis. The available evidence clearly demonstrates that these molecules are intertwined with cellular pathways regulated by classical oncogenes and tumor suppressors such as MYC, RAS and p53. Incorporation of miRNA regulation into current models of molecular cancer pathogenesis will be essential to achieve a complete understanding of this group of diseases.

Animals↗
PubMed2002

MicroRNA maturation: stepwise processing and subcellular localization.

MicroRNAs (miRNAs) constitute a novel, phylogenetically extensive family of small RNAs ( approximately 22 nucleotides) with potential roles in gene regulation. Apart from the finding that miRNAs are produced by Dicer from the precursors of approximately 70 nucleotides (pre-miRNAs), little is known about miRNA biogenesis. Some miRNA genes have been found in close conjunction, suggesting that they are expressed as single transcriptional units. Here, we present in vivo and in vitro evidence that these clustered miRNAs are expressed polycistronically and are processed through at least two sequential steps: (i) generation of the approximately 70 nucleotide pre-miRNAs from the longer transcripts (termed pri-miRNAs); and (ii) processing of pre-miRNAs into mature miRNAs. Subcellular localization studies showed that the first and second steps are compartmentalized into the nucleus and cytoplasm, respectively, and that the pre-miRNA serves as the substrate for nuclear export. Our study suggests that the regulation of miRNA expression may occur at multiple levels, including the two processing steps and the nuclear export step. These data will provide a framework for further studies on miRNA biogenesis.

Biological Transport↗
PubMed2006

Molecular correlates of site-specific metastasis.

Metastasis is the spread of tumor cells from a primary site to distant organs. It is the major cause of cancer morbidity and death. In the last few decades, significant advances have been made in surgical techniques, radiation therapy delivery, and chemotherapy including the development of combination regimens and agents inhibiting newly characterized biological targets. Treatment of metastasis, however, remains the most challenging task in cancer therapy because metastatic growth relies on complex interactions between tumor cells and the host and is often resistant to all therapeutic modalities. Management of metastasis in bone is especially challenging given the difficulty of access for therapeutic agents. Contemporary research seeks to explain the striking organ specificity observed in metastasis. In this article, we will examine historic perspectives on site-specific metastasis and review cellular and molecular evidence pertinent to the mechanisms of organ specificity. We will discuss a number of studies that aim to identify gene signatures correlating with organ-selective metastasis using microarray technology. Lastly, we will discuss potential areas of future research including microRNAs, proteomics, and the development of diagnostic and therapeutic interventions.

Animals↗
PubMed2006

MicroRNAs in biological processes and carcinogenesis.

MicroRNAs (miRNAs) encoding small non-coding RNAs have been recognized as a very large gene family present in most organisms. The precise biological effects of miRNAs are yet to be elucidated in detail, partly because each miRNA is believed to negatively regulate the expression of hundreds of target genes. Nevertheless, recent findings indicate that carcinogenic processes are associated with alterations in the expression of several miRNAs, suggesting that some function as oncogenes or tumor suppressor genes. The present review focuses on recent findings in this exciting new area of research, with special emphasis on the involvement of miRNAs in cancer development and progression. Further studies are clearly warranted to elucidate the molecular and biological roles of miRNAs, which may ultimately provide both a better understanding of disease development, as well as a foundation for novel strategies for cancer diagnosis and therapy.

Animals↗
PubMed2003

Short hairpin type of dsRNAs that are controlled by tRNA(Val) promoter significantly induce RNAi-mediated gene silencing in the cytoplasm of human cells.

The post-transcriptional gene silencing in animals and plants is called RNA interference (RNAi). Guides for the sequence-specific degradation of mRNA are 21-nt small interfering RNAs (siRNAs) that are generated by Dicer-dependent cleavage from longer double-stranded RNAs (dsRNAs). To examine the relationship between the localization of dsRNA and the target cleavage of RNAi in human cells, we constructed five kinds of dsRNA expression vector that were controlled by tRNA(Val) or U6 promoter. Transcripts of tRNA-dsRNA were consistently localized in the cytoplasm and were efficiently processed by Dicer. In contrast, transcripts of tRNA-dsRNA were not processed in cells that expressed Dicer-directed ribozymes. In addition, transcripts of U6-dsRNA were basically localized in the nucleus and were not significantly processed, unless the transcripts of U6-dsRNAs possessed a microRNA-based loop motif: in the latter case, U6-dsRNAs with a microRNA-based loop were transported to the cytoplasm and were effectively processed. More over, tRNA-dsRNA directed against a mutant k-ras transcript cleaved its target mRNA efficiently in assays of RNAi not only in vitro with a cytoplasmic extract but also in vivo. Therefore, it appears that RNAi in human cells occur in the cytoplasm. Importantly, the same tRNA-dsRNA did not affect the degradation of the normal k-ras mRNA in vitro and in vivo. Our tRNA-dsRNA technology should be a powerful tool for studies of the mechanism of RNAi and the functions of various genes in mammalian cells with potential utility as a therapeutic agent.

Cell Division↗
PubMed2005

Cloning and identification of a microRNA cluster within the latency-associated region of Kaposi's sarcoma-associated herpesvirus.

MicroRNAs (miRNAs) are small, noncoding regulatory RNA molecules that bind to 3' untranslated regions (UTRs) of mRNAs to either prevent their translation or induce their degradation. Previously identified in a variety of organisms ranging from plants to mammals, miRNAs are also now known to be produced by viruses. The human gammaherpesvirus Epstein-Barr virus has been shown to encode miRNAs, which potentially regulate both viral and cellular genes. To determine whether Kaposi's sarcoma-associated herpesvirus (KSHV) encodes miRNAs, we cloned small RNAs from KSHV-positive primary effusion lymphoma-derived cells and endothelial cells. Sequence analysis revealed 11 isolated RNAs of 19 to 23 bases in length that perfectly align with KSHV. Surprisingly, all candidate miRNAs mapped to a single genomic locale within the latency-associated region of KSHV. These data suggest that viral and host cellular gene expression may be regulated by miRNAs during both latent and lytic KSHV replication.

Cloning, Molecular↗
PubMed2005

microRNA172 down-regulates glossy15 to promote vegetative phase change in maize.

Shoot development in many higher plant species is characterized by phase change, where meristems and organs transition from one set of identities to another. The transition from a juvenile to adult leaf identity in maize is regulated by the APETALA2-like gene glossy15 (gl15). We demonstrate here that increasing gl15 activity in transgenic maize not only increases the number of leaves expressing juvenile traits, but also delays the onset of reproductive development, indicating that gl15 plays a primary role in the maintenance of the juvenile phase. We also show that the accumulation of a maize microRNA homologous to miR172 increases during shoot development and mediates gl15 mRNA degradation. These data indicate that vegetative phase change in maize is regulated by the opposing actions of gl15 and miR172, with gl15 maintaining the juvenile phase and miR172 promoting the transition to the adult phase by down-regulation of gl15. Our results also suggest that the balance of activities between APETALA2-like genes and miR172 may be a general mechanism for regulating vegetative phase change in higher plants.

Base Sequence↗
PubMed2006

Relief of microRNA-mediated translational repression in human cells subjected to stress.

In metazoans, most microRNAs imperfectly base-pair with the 3' untranslated region (3'UTR) of target mRNAs and prevent protein accumulation by either repressing translation or inducing mRNA degradation. Examples of specific mRNAs undergoing microRNA-mediated repression are numerous, but whether the repression is a reversible process remains largely unknown. Here we show that cationic amino acid transporter 1 (CAT-1) mRNA and reporters bearing its 3'UTR can be relieved from the microRNA miR-122-induced inhibition in human hepatocarcinoma cells subjected to different stress conditions. The derepression of CAT-1 mRNA is accompanied by its release from cytoplasmic processing bodies and its recruitment to polysomes. The derepression requires binding of HuR, an AU-rich-element binding protein, to the 3'UTR of CAT-1 mRNA. We propose that proteins interacting with the 3'UTR will generally act as modifiers altering the potential of miRNAs to repress gene expression.

3' Untranslated Regions↗