Triple-negative breast cancer (TNBC) is a rapidly recurring and highly metastatic malignancy with high heterogeneity and chemoradiotherapy resistance. Chronic unpredictable mild stress (CUMS) can ...induce the occurrence of tumors and enhance lymphatic infiltration and distant metastasis through direct interaction with the sympathetic nervous system; however, its relevance in TNBC is yet to be clarified. In this study, DARS-AS1, a newly reported CUMS-responsive lncRNA, was found to be enriched in TNBC clinical tumors and cells and positively correlated with late clinical stage in patients with TNBC. DARS-AS1 overexpression significantly enhanced the migration and invasion of TNBC tumors by inhibiting miR-129-2-3p and upregulated CDK1 to activate the NF-κB/STAT3 signaling pathway both in vitro and in vivo. Treatment with DARS-AS1 siRNA-loaded exosomes (EXOs) substantially slowed CUMS-induced TNBC cell growth and liver metastasis. Therefore, DARS-AS1 represents a potential therapeutic target for metastatic TNBC, and EXOs may serve as siRNA delivery carriers in clinical therapy.
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•Exosomes are natural nanocarriers for efficient delivery of siRNA to recipient cells.•SiRNA-loaded exosomes were performed by modified calcium-mediated transfection method.•SiRNA-loaded exosomes demonstrated dose-dependent knockdown efficiency.•SiRNA-loaded exosomes showed strong antitumor activity on TNBC cells in vitro.•SiRNA-loaded exosomes intensively inhibited TNBC tumor growth and metastasis in vivo.
Long non-coding RNAs have emerged as important players in cancer biology. Increasing evidence has uncovered their potency in improving cancer management as they can be used as a credible prognostic ...and diagnostic biomarker. Recently, DARS-AS1 has gained significant attention for its involvement in facilitating tumor progression. So far, numerous research has been reported its upregulation in different malignancies of human body systems and revealed its association with cancer hallmarks as well as clinicopathological characteristics. Importantly, targeting DARS-AS1 holds promise in cancer therapy. In the current study, we provide an in-depth analysis of its expression status and explore the underlying mechanisms through which DARS-AS1 contributes to tumor initiation, growth, invasion, and metastasis. Additionally, we examine the correlation between DARS-AS1 expression and clinicopathological features of cancer patients, shedding light on its potential as a cancer biomarker. Furthermore, we discuss the therapeutic potential of targeting DARS-AS1 in cancer treatment, highlighting emerging strategies, such as RNA interference and small molecule inhibitors. Boosting the understanding of its functional role can open new avenues for precision medicine, thus resulting in better outcomes for cancer patients.
This review summarizes the mechanisms of the initiator protein DnaA in replication initiation and its regulation in
. The chromosomal origin (
) DNA is unwound by the replication initiation complex ...to allow loading of DnaB helicases and replisome formation. The initiation complex consists of the DnaA protein, DnaA-initiator-associating protein DiaA, integration host factor (IHF), and
, which contains a duplex-unwinding element (DUE) and a DnaA-oligomerization region (DOR) containing DnaA-binding sites (DnaA boxes) and a single IHF-binding site that induces sharp DNA bending. DiaA binds to DnaA and stimulates DnaA assembly at the DOR. DnaA binds tightly to ATP and ADP. ATP-DnaA constructs functionally different sub-complexes at DOR, and the DUE-proximal DnaA sub-complex contains IHF and promotes DUE unwinding. The first part of this review presents the structures and mechanisms of
-DnaA complexes involved in the regulation of replication initiation. During the cell cycle, the level of ATP-DnaA level, the active form for initiation, is strictly regulated by multiple systems, resulting in timely replication initiation. After initiation, regulatory inactivation of DnaA (RIDA) intervenes to reduce ATP-DnaA level by hydrolyzing the DnaA-bound ATP to ADP to yield ADP-DnaA, the inactive form. RIDA involves the binding of the DNA polymerase clamp on newly synthesized DNA to the DnaA-inactivator Hda protein. In
-dependent DnaA-ATP hydrolysis (DDAH), binding of IHF at the chromosomal locus
, which contains a cluster of DnaA boxes, results in further hydrolysis of DnaA-bound ATP. SeqA protein inhibits untimely initiation at
by binding to newly synthesized
DNA and represses
transcription in a cell cycle dependent manner. To reinitiate DNA replication, ADP-DnaA forms oligomers at DnaA-reactivating sequences (
and
), resulting in the dissociation of ADP and the release of nucleotide-free apo-DnaA, which then binds ATP to regenerate ATP-DnaA.
plays an important role in this process and its activation is regulated by timely binding of IHF to
in the cell cycle. Chromosomal locations of
sites are optimized for the strict regulation for timely replication initiation. The last part of this review describes how DDAH and DARS regulate DnaA activity.
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Clear cell renal cell carcinoma (ccRCC), the most frequent subtype of renal cell carcinoma (RCC), is characterized by high relapse rate and mortality. Long non-coding RNAs (lncRNAs) ...are critical participants during cancer development. LncRNA DARS antisense RNA 1 (DARS-AS1), a newly-found lncRNA, is not specifically reported in ccRCC. However, Gene Expression Profiling Interactive Analysis (GEPIA) and starBase databases revealed the up-regulation of DARS-AS1 in ccRCC. Current study investigated the function and mechanism of DARS-AS1 in ccRCC. Functional assays including colony formation assay, EdU assay, caspase-3 activity detection, flow cytometry analysis and JC-1 assay were implemented to identify the role of DARS-AS1 in ccRCC. As a result, silencing of DARS-AS1 retarded proliferation and facilitated apoptosis in ccRCC cells. Moreover, mainly a cytoplasmic localization of lncRNA DARS-AS1 was verified in ccRCC cells. Then, we demonstrated that DARS-AS1 positively regulated its nearby gene, aspartyl-tRNA synthetase (DARS), by sequestering miR-194−5p. Moreover, DARS was testified as the oncogene in ccRCC and DARS-AS1 worked as a tumor-facilitator in ccRCC through miR-194−5p/DARS signaling. In a summary, this study firstly uncovered that DARS-AS1 boosted DARS expression via absorbing miR-194−5p, therefore contributing to malignancy in ccRCC. Our findings may be helpful for opening new strategies for ccRCC treatment.
Long noncoding RNAs (LncRNAs) have been gaining attention as potential therapeutic targets for lung cancer. In this study, we investigated the expression and biological behavior of lncRNA DARS‐AS1, ...its predicted interacting partner miR‐302a‐3p, and ACAT1 in nonsmall cell lung cancer (NSCLC). The transcript level of DARS‐AS1, miR‐302a‐3p, and ACAT1 was analyzed using qRT‐PCR. Endogenous expression of ACAT1 and the expression of—and changes in—AKT/ERK pathway‐related proteins were determined using western blotting. MTS, Transwell, and apoptosis experiments were used to investigate the behavior of cells. The subcellular localization of DARS‐AS1 was verified using FISH, and its binding site was verified using dual‐luciferase reporter experiments. The binding of DARS‐AS1 to miR‐302a‐3p was verified using RNA co‐immunoprecipitation. In vivo experiments were performed using a xenograft model to determine the effect of DARS‐AS1 knockout on ACAT1 and NSCLC. lncRNA DARS‐AS1 was upregulated in NSCLC cell lines and tissues and the expression of lncRNA DARS‐AS1 was negatively correlated with survival of patients with NSCLC. Knockdown of DARS‐AS1 inhibited the malignant behaviors of NSCLC via upregulating miR‐302a‐3p. miR‐302a‐3p induced suppression of malignancy through regulating oncogene ACAT1. This study demonstrates that the DARS‐AS1‐miR‐302a‐3p‐ACAT1 pathway plays a key role in NSCLC.
Cervical cancer (CC) is one of the most prevalent malignancies among females. Cytoprotective autophagy could confer cancer cell tolerance to hypoxic stress, promoting cell survival and adaptation. ...Aspartyl-tRNA synthetase 1 antisense 1 (DARS-AS1) is an oncogenic long non-coding RNA (lncRNA) in various cancers, but how DARS-AS1 regulates cytoprotective autophagy in hypoxic environment in CC remains unclear. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted to explore the interaction between hypoxia-inducible factor 1 subunit alpha (HIF1α) and DARS-AS1 promoter. Methylated RNA immunoprecipitation (MeRIP) followed by quantitative real-time polymerase-chain reaction (RT-qPCR) detected methylated RNA level. The process of autophagic maturation was monitored by immunofluorescence staining. Higher DARS-AS1 expression was found in CC tissues and cytoprotective. We also uncovered that hypoxic exposure induced cytoprotective autophagy via HIF1α/DARS-AS1/DARS axis. Moreover, DARS-AS1 was validated to facilitate DARS translation via recruiting N6-adenosine-methyltransferase methyltransferase like 3 (METTL3) and methyltransferase like 14 (METTL14), which bound with DARS mRNA DARS mRNA 5' untranslated region (5ʹUTR) and promoting its translation. The present study demonstrated that the 'HIF1α/DARS-AS1/DARS/ATG5/ATG3' pathway regulated the hypoxia-induced cytoprotective autophagy of CC and might be a promising target of therapeutic strategies for patients afflicted with CC.
Ovarian cancer is a malignant tumor with a poor prognosis, its underlying mechanism is still unclear.
In this study, long noncoding RNA DARS-AS1 was studied to identify its function in the ...development of ovarian cancer.
Perform functional experiments to detect the effects of DARS-AS1 on the proliferation, apoptosis, and migration of ovarian cancer cells A2780. The luciferase report, immunoprecipitation (IP) experiment, and ubiquitination level determination verify that RBX1 ubiquitination and mediate the degradation of tumor suppressor gene TP53.
Knockdown of DARS-AS1 can inhibit cell proliferation, migration, and apoptosis, and the application of miR-194-5p inhibitors can prevent this process. Luciferase and IP experiments showed that DARS-AS1 regulates the expression of RBX1 by binding to miR-194-5p, and RBX1 mediates its degradation through ubiquitination of TP53.
In our present study, we have synthesized polycrystalline ceramics with the chemical composition Ba0.97La0.02Ti(1-x)Nb4x/5O3, denoted as BLTi1-xNb4x/5, where x takes on various values, including ...0.00, 0.02, 0.05, 0.07, and 0.10. The materials were prepared through a molten salt method, followed by the formation of powders into pellets, and subsequent sintering at 800 °C for 24 h in the air. Through X-ray diffractometer (XRD), we confirmed that the synthesized ceramics exhibited a tetragonal perovskite structure, and they were found to be in a single phase. Surface characteristics were determined using Scanning Electron Microscopy (SEM). Raman spectroscopic investigations further verified the tetragonal perovskite structure of our materials. Additionally, this analysis revealed the successful incorporation of La3+ ions in place of Ba2+ ions within the A-site and Nb5+ ions substituting for Ti4+ ions within the B-site of the BT lattice. Notably, our study demonstrated the capability to adjust the Raman shifts of essential optical modes. While the majority of Raman shifts remained unchanged, La and Nb doping had a significant impact specifically on the A1TO3 mode. This mode is associated with the deformation of the oxygen octahedron centered on the central Ti ion, indicating that the influence of these dopant ions primarily pertains to the B-site of the material.
•Ba0.97La0.02Ti1-xNb4x/5O3 was prepared by molten-salt method.•The compounds crystallize in the tetragonal structure with P4/mmm space group.•Raman spectroscopy revealed that all samples exhibit the tetragonal perovskite phase with P4/mmm symmetry.•The presences of extra Raman modes are connected with lattice disorder and imperfections.•The extra modes give knowledge into changes from chemical substitutions in our compounds.
Chromatin organization and transcriptional profiles undergo tremendous reordering during senescence. However, uncovering the regulatory mechanisms between chromatin reconstruction and gene expression ...in senescence has been elusive. Here, we depicted the landscapes of both chromatin accessibility and gene expression to reveal gene regulatory networks in human umbilical vein endothelial cell (HUVEC) senescence and found that chromatin accessibilities are redistributed during senescence. Particularly, the intergenic chromatin was massively shifted with the increased accessibility regions (IARs) or decreased accessibility regions (DARs), which were mainly enhancer elements. We defined AP‐1 transcription factor family as being responsible for driving chromatin accessibility reconstruction in IARs, where low DNA methylation improved binding affinity of AP‐1 and further increased the chromatin accessibility. Among AP‐1 transcription factors, we confirmed ATF3 was critical to reconstruct chromatin accessibility to promote cellular senescence. Our results described a dynamic landscape of chromatin accessibility whose remodeling contributes to the senescence program, we identified that AP‐1 was capable of reorganizing the chromatin accessibility profile to regulate senescence.
Senescence‐specific increased accessibility regions (IARs) are involved in senescence regulation. The gene regulatory network is rewired during senescence, a process possibly determined by chromatin accessibility remodeling. DNA methylation is negatively correlated with chromatin accessibility, and loss of DNA methylation may help establish chromatin accessibility. The AP‐1 family, especially ATF3, is a potential regulator that remodels the accessibility in IARs in HUVEC senescence and that may be an effective target for senescence intervention.
DARS, encoding for aspartyl-tRNA synthetase, is implicated in the pathogenesis of various cancers, including renal cell carcinoma, glioblastoma, colon cancer, and gastric cancer. Its role in ...BCR/ABL1-negative myeloproliferative neoplasms (MPNs), however, remains unexplored. This study aimed to elucidate the expression of DARS in patients with MPNs (PV 23, ET 19, PMF 16) through immunohistochemical analysis and to examine the profiles of circulating immune cells and cytokines using flow cytometry. Our findings indicate a significant overexpression of DARS in all MPNs subtypes at the protein level compared to controls (P < 0.05). Notably, elevated DARS expression was linked to splenomegaly in MPNs patients. The expression of DARS showed a negative correlation with CD4+ T cells (R = − 0.451, P = 0.0004) and CD4+ T/CD8+ T cell ratio (R = − 0.3758, P = 0.0040), as well as with CD68+ tumor-associated macrophages (R = 0.4037, P = 0.0017). Conversely, it was positively correlated with IL-2 (R = 0.5419, P < 0.001), IL-5 (R = 0.3161, P = 0.0166), IL-6 (R = 0.2992, P = 0.0238), and IFN-γ (R = 0.3873, P = 0.0029). These findings underscore a significant association between DARS expression in MPNs patients and specific clinical characteristics, as well as immune cell composition. Further investigation into the interplay between DARS and the immune microenvironment in MPNs could shed light on the underlying mechanisms of MPNs pathogenesis and immune dysregulation.
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