RNA Biology最新文献

Cervical cancer is a leading cause of cancer-related deaths, with cervical squamous cell carcinoma (CSCC) accounting for a majority of cases. Circular RNAs (circRNAs) have been repeatedly suggested as crucial effectors in modulating the development of multiple malignancies. The expression of circ_0002762 was predicted to be high in CSCC tissues in GEO dataset, but the functional role and underlying regulatory mechanism of circ_0002762 in CSCC was unclear. By series of functional assays and mechanism assays, supported by bioinformatics analysis, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) analysis and western blot assays, we identified that circ_0002762 aberrantly up-regulated in CSCC, promoting CSCC cell migration and invasion. Mechanically, circ_0002762 was transcriptionally activated by Fork head box A1 (FOXA1). Moreover, the involvement of nuclear factor kappa B (NF-kB) signalling in circ_0002762 regulation mechanism in CSCC cells was ascertained. Additionally, circ_0002762, predominantly accumulated in cell cytoplasm, was proved to recruit Mov10 RISC complex RNA helicase (MOV10) to enhance RelA mRNA stability, thus affecting CSCC cell migration and invasion. In summary, FOXA1-mediated circ_0002762 up-regulation could enhance the migratory and invasive abilities of CSCC cells via the MOV10/RelA/NF-kB pathway.

Complete nerve regeneration is limited in current therapeutic approaches for spinal cord injuries (SCIs) and peripheral nerve injuries (PNIs). Extracellular vesicles (EVs) and microRNAs (miRNAs) play a pivotal role in intercellular communication by transporting various biomolecules, including miRNAs, to the recipient cells. Thus, they are promising targets for novel neural regeneration drugs. This comprehensive study examined the roles of EV-derived miRNAs in facilitating neural rejuvenation after SCI and PNI. It also explored the mechanisms by which they augment neuroprotection and promote cell viability. It also discusses their translational potential for treating nerve injury and evaluates their potential impact on advancements in nerve resurrection and prospective research in regenerative medicine. The findings may provide effective treatments and improve outcomes, as well as contribute to addressing the direction for the next studies, for the pathologies of SCI and PNI.

Over the past decade, non-coding RNAs (ncRNAs) have gained prominence in research due to their widespread presence in cells, yet their functions remain increasingly complex and less understood. Despite being initially deemed 'junk', many lncRNAs are now recognized as key regulators in cells and are often affected in disease contexts. Notably, numerous mRNAs have annotated antisense RNAs (asRNAs). Because asRNAs resemble the largest group of lncRNAs and were identified to serve a general function in Saccharomyces cerevisiae, they are the focus of this review. In S. cerevisiae, the absence of RNA interference (RNAi) enables unbiased study and allowed researchers to investigate their roles in gene regulation more directly with intriguing results, summarized here. Expression of asRNA leads to the formation of double-stranded RNAs (dsRNAs) with the regarding sense counterpart, resulting in enhanced gene expression through preferential nuclear export. Thus, these hidden leaders can boost gene expression and require future attention pivotal for elucidating their influence on biological processes and revealing disease mechanisms.

There is no life without RNA or lipids. But could there be life with only RNA and lipids? The discovery that RNA can catalyse reactions in addition to encoding information opened new directions for engineering life and the possibility of life emerging from an RNA World. But a key missing ingredient for RNA-based biochemical systems is a mechanism to organize RNAs and regulate their activity. Lipids, which are essential for life and one of the most ancient biomolecules, can spontaneously self-assemble to form membranous bilayers, theoretically providing a surface that can serve to concentrate, protect, and regulate RNAs. This review explores the interactions between RNA and lipids, including the chemical basis for their interactions, and the implications for synthetic biology, RNA World, and modern cell biology. We discuss observations that RNA can selectively bind to lipid membranes in a sequence-dependent manner, and entertain how these interactions might be employed to engineer RNA-based sensors and regulatory elements in synthetic systems. The emerging field of RNA-lipid interactions opens new possibilities for engineering orthogonal biochemistries for synthetic cells, innovations in RNA therapeutics, and discovering potentially new facets of cellular regulation.

The crosstalk between the tumour immune microenvironment (TIME) and tumour cells promote immune evasion and resistance to immunotherapy in gastrointestinal (GI) tumours. Post-transcriptional regulation of genes is pivotal to GI tumours progression, and RNA-binding proteins (RBPs) serve as key regulators via their RNA-binding domains. RBPs may exhibit either anti-tumour or pro-tumour functions by influencing the TIME through the modulation of mRNAs and non-coding RNAs expression, as well as post-transcriptional modifications, primarily N6-methyladenosine (m⁶A). Aberrant regulation of RBPs, such as HuR and YBX1, typically enhances tumour immune escape and impacts prognosis of GI tumour patients. Further, while targeting RBPs offers a promising strategy for improving immunotherapy in GI cancers, the mechanisms by which RBPs regulate the TIME in these tumours remain poorly understood, and the therapeutic application is still in its early stages. This review summarizes current advances in exploring the roles of RBPs in regulating genes expression and their effect on the TIME of GI tumours, then providing theoretical insights for RBP-targeted cancer therapies.

Aberrantly expressed microRNA-4484 (miR-4484) has recently garnered attention for its involvement in human diseases, but its specific role in hepatocellular carcinoma (HCC) remains largely unexplored. This study investigates the function of miR-4484 in HCC progression and its regulatory interaction with KIF2C. Analysis of the data from the TCGA-LIHC database revealed that miR-4484 expression is significantly downregulated in HCC tissues, with lower levels correlating with worse prognosis. In vitro experiments confirmed that miR-4484 expression is lower in HCC cell lines compared to a normal liver cell line. Functional assays demonstrated that miR-4484 overexpression via a miR-4484 mimic suppressed cell proliferation and induced G1 phase arrest, whereas miR-4484 inhibition promoted proliferation and facilitated cell cycle progression from G1 to S and G2 phases. Additionally, KIF2C expression was significantly upregulated in HCC tissues and cell lines, exhibiting an inverse correlation with miR-4484 levels. Dual-Luciferase Reporter Assays confirmed that miR-4484 directly binds to KIF2C, thereby regulating its expression and influencing cell proliferation and cell cycle progression. In vivo, subcutaneous intratumoral injection of the miR-4484 mimic in nude mice significantly inhibited HCC tumour growth. These findings highlight miR-4484 as a potential tumour suppressor in HCC through its direct targeting of KIF2C, underscoring its promise as a therapeutic target for HCC treatment.

The Fragile X Messenger Ribonucleoprotein (FMRP) is a selective RNA-binding protein that localizes to the cytoplasm and the nucleus. The loss of FMRP results in Fragile X Syndrome (FXS), an autism spectrum disorder. FMRP interacts with ribosomes and regulates the translation of mRNAs essential for neuronal development and synaptic plasticity. However, the biochemical nature of this translation regulation is unknown. Here, we report that a potential feature of FMRP-mediated translation regulation during neuronal differentiation is the modulation of 2'-O-methylation of ribosomal RNA. 2'O-methylation, facilitated by C/D box snoRNAs in the nucleus, is a major epitranscriptome mark on rRNA, essential for ribosome assembly and function. We found that FMRP influences a distinct rRNA 2'O-Methylation pattern across neuronal differentiation. We show that in H9 ESCs, FMRP interacts with a selected set of C/D box snoRNA in the nucleus, resulting in the generation of ribosomes with a distinct pattern of rRNA 2'O-Methylation. This epitranscriptome pattern on rRNA undergoes a significant change during the differentiation of ESCs to neuronal precursors and cortical neurons. ESCs exhibit substantial levels of hypomethylated residues on rRNA, which progressively decrease in neuronal precursors and post-mitotic cortical neurons. This reduction correlates with changes in global protein synthesis across different stages of differentiation. Importantly, this stepwise change in the 2'O-methylation pattern during neuronal differentiation is altered in the absence of FMRP, which could impact neuronal development and contribute to dysregulated protein synthesis observed in Fragile X Syndrome.

DEAH box splicing helicase Prp16 in budding yeast governs spliceosomal remodelling from the branching conformation (C complex) to the exon ligation conformation (C* complex). In this study, we examined the genome-wide functions of Prp16 in the short intron-rich genome of the basidiomycete yeast Cryptococcus neoformans. The presence of multiple introns per transcript with intronic features that are more similar to those of higher eukaryotes makes it a promising model for studying spliceosomal splicing. Using a promoter-shutdown conditional Prp16 knockdown strain, we uncovered genome-wide but substrate-specific roles in C. neoformans splicing. The splicing functions of Prp16 are dependent on helicase motifs I and II, which are conserved motifs for helicase activity. A small subset of introns spliced independent of Prp16 activity was investigated to discover that exonic sequences at the 5' splice site (5'SS) and 3' splice site (3'SS) with stronger affinity for U5 loop 1 are a common feature in these introns. Furthermore, short (60-100nts) and ultrashort introns (<60nts) prevalent in the C. neoformans transcriptome were more sensitive to Prp16 knockdown than longer introns, indicating that Prp16 is required for the efficient splicing of short and ultrashort introns. We propose that stronger U5 snRNA-pre-mRNA interactions enable efficient transition of the spliceosome from the first to the second catalytic confirmation in Prp16 knockdown, particularly for short introns and introns with suboptimal features. This study provides insights into fine-tuning spliceosomal helicase function with variations in cis-element features.

The Long Interspersed Element-1 (LINE-1) contributes significantly to carcinogenesis and to tumour heterogeneity in many cancer types, including hepatocellular carcinoma (HCC), by its autonomous retrotransposition (RTP) and by its ability to retrotranspose some non-autonomous transposable elements. Previously, multiple proteins and a few microRNAs (miRs) were described as regulators of LINE-1 RTP. Here, we demonstrate that miR-222, which is oncogenic in HCC, promotes LINE-1 RTP in human HCC and some other cell lines in vitro, and that both miR-222-3p and miR-222-5p activate LINE-1 RTP in a cell-type specific manner. We generated miR-222-knockout mutants of the Huh7 and FLC4 hCC cell lines, and performed RNA-seq analysis of Huh7/miR-222-knockout cells and global proteomics analysis of both Huh7 and FLC4 miR-222-knockout mutants. We demonstrate that miR-222 decreases let-7c expression in both Huh7 and FLC4 cells, and that this decrease contributes to promotion of LINE-1 RTP by miR-222 in Huh7 cells.

Protein kinase R (PKR) is a serine/threonine kinase that recognizes double-stranded RNAs (dsRNAs) to initiate innate immune signalling during viral infection. PKR dimerizes on long dsRNAs and undergoes autophosphorylation. Phosphorylated/Activated PKR then catalyses the phosphorylation of numerous substrates to control global translation, inflammatory response, and cell signalling pathways. While primarily known for its antiviral role, emerging evidence suggests that PKR can play multifaceted roles in uninfected cells by interacting with cellular dsRNAs and protein regulators. The misactivation of PKR in uninfected cells is associated with many degenerative and inflammatory diseases. Even in healthy cells, PKR can affect gene expression by controlling mRNA splicing and gene-specific translation under stress. In addition, PKR can modulate cell cycle progression and promote cellular differentiation in several tissue types. This review explores PKR function in various pathological and physiological contexts in the absence of viral stimuli. By elucidating these diverse functions, we aim to highlight the perspectives in cellular dsRNA research and the therapeutic implications of targeting PKR, stimulating further research into this versatile and essential RNA-dependent kinase.