scholarly journals LncRNA NR038975, A Serum-Based Biomarker, Promotes Gastric Tumorigenesis by Interacting With NF90/NF45 Complex

2021 ◽  
Vol 11 ◽  
Author(s):  
Sisi Wei ◽  
Suli Dai ◽  
Cong Zhang ◽  
Ruinian Zhao ◽  
Zitong Zhao ◽  
...  
Keyword(s):  
Diagnostic Marker ◽  
Subcellular Location ◽  
Potential Therapeutic Target ◽  
Interactive Analysis ◽  
Genetic Deficiency ◽  
Rna Immunoprecipitation ◽  
Full Length Sequence ◽  
The Stability ◽  
Serum Exosomes ◽  
Independent Cohort

Gastric cancer (GC) is one of the deadliest cancers, and long noncoding RNAs (lncRNAs) have been reported to be the important regulators during the occurrence and development of GC. The present study identified a novel and functional lncRNA in GC, named NR038975, which was confirmed to be markedly upregulated in the Gene Expression Profiling Interactive Analysis (GEPIA) dataset and our independent cohort of GC tissues. We firstly characterized the full-length sequence and subcellular location of NR038975 in GC cells. Our data demonstrated that upregulated NR038975 expression was significantly related to lymph node metastasis and TNM stage. In addition, knockdown of NR038975 inhibited GC cell proliferation, migration, invasion, and clonogenicity and vice versa. Mechanistically, RNA pull-down and mass spectrometry assays identified the NR038975-binding proteins and NF90/NF45 complex, and the binding was also confirmed by RNA immunoprecipitation and confocal experiments. We further demonstrated that genetic deficiency of NR038975 abrogated the interaction between NF45 and NF90. Moreover, NF90 increased the stability of NR038975. Thus, NR038975-NF90/NF45 will be an important combinational target of GC. Finally, we detected NR038975 in serum exosomes and serum of GC patients. Our results indicated that NR038975 was a biomarker for gastric tumorigenesis. The current study demonstrated that NR038975 is a novel lncRNA that is clinically and functionally engaged in GC progression and might be a novel diagnostic marker and potential therapeutic target.

scholarly journals A single synonymous mutation determines the phosphorylation and stability of the nascent protein

2018 ◽  
Vol 11 (3) ◽  
pp. 187-199 ◽  
Author(s):  
Konstantinos Karakostis ◽  
Sivakumar Vadivel Gnanasundram ◽  
Ignacio López ◽  
Aikaterini Thermou ◽  
Lixiao Wang ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
P53 Protein ◽  
Intrinsically Disordered Protein ◽  
Subcellular Location ◽  
Genotoxic Stress ◽  
Synonymous Mutation ◽  
Atm Kinase ◽  
Intrinsically Disordered ◽  
The Stability ◽  
P53 Mrna

Abstract p53 is an intrinsically disordered protein with a large number of post-translational modifications and interacting partners. The hierarchical order and subcellular location of these events are still poorly understood. The activation of p53 during the DNA damage response (DDR) requires a switch in the activity of the E3 ubiquitin ligase MDM2 from a negative to a positive regulator of p53. This is mediated by the ATM kinase that regulates the binding of MDM2 to the p53 mRNA facilitating an increase in p53 synthesis. Here we show that the binding of MDM2 to the p53 mRNA brings ATM to the p53 polysome where it phosphorylates the nascent p53 at serine 15 and prevents MDM2-mediated degradation of p53. A single synonymous mutation in p53 codon 22 (L22L) prevents the phosphorylation of the nascent p53 protein and the stabilization of p53 following genotoxic stress. The ATM trafficking from the nucleus to the p53 polysome is mediated by MDM2, which requires its interaction with the ribosomal proteins RPL5 and RPL11. These results show how the ATM kinase phosphorylates the p53 protein while it is being synthesized and offer a novel mechanism whereby a single synonymous mutation controls the stability and activity of the encoded protein.

scholarly journals N6-methyladenosine Reader YTHDF1-induced lncRNA DLGAP1-AS2 Promotes the c-Myc Mediated Gastric Cancer Aerobic Glycolysis

2021 ◽  
Author(s):  
Changshun Yang ◽  
Yu Zhang ◽  
Xuefei Cheng ◽  
Weihua Li
Keyword(s):  
Gastric Cancer ◽  
Aerobic Glycolysis ◽  
Profile Data ◽  
Extracellular Acidification ◽  
Rna Immunoprecipitation ◽  
Non Coding Rnas ◽  
Essential Function ◽  
The Stability ◽  
Rip Assay ◽  
Advanced Pathological Stage

Abstract Background: Emerging data has demonstrated the essential function of N6-methyladenosine (m6A) modification of long non-coding RNAs (lncRNAs) in human tumorigenesis. Nevertheless, the regulation of m6A-lncRNA approach on gastric cancer (GC) tumorigenesis is unclear. Methods: LncRNA expression profile data was derived from GEO. M6A profile was screened using Methylated RNA immunoprecipitation sequencing (MeRIP-Seq). The metabolism assays were conducted using quantitative analysis of glucose, lactate, ATP and extracellular acidification rate (ECAR). The m6A level of specific RNA was identified using MeRIP-qPCR. The molecular interaction was detected using RIP assay.Results: In the findings, results showed that enhanced DLGAP1-AS2 expression was correlated with advanced pathological stage and poor prognosis. Functionally, DLGAP1-AS2 promoted the aerobic glycolysis and knockdown of DLGAP1-AS2 suppressed the tumor growth of GC cells. Mechanistically, m6A reader YTHDF1 accelerated the enrichment of DLGAP1-AS2 in GC. Moreover, DLGAP1-AS2 interacted with YTHDF1 to integrate c-Myc mRNA, thereby enhancing the stability of c-Myc mRNA through DLGAP1-AS2/m6A/YTHDF1/c-Myc mRNA. Conclusions: In conclusion, our work indicates a novel m6A-maintained lncRNA DLGAP1-AS2 in the GC aerobic glycolysis, disclosing a m6A-reader-dependent modality regulation.

scholarly journals CRT Silencing Inhibits ECM Synthesis in HGFs Cultured on Three-Dimensional PLGA Scaffolds Via Inhibiting The CaN/NFAT3 Signalling Pathway

2021 ◽  
Author(s):  
Hui Wei ◽  
Zhixing Chen ◽  
Hsuyin Min ◽  
Qinqin Ma ◽  
Yuting You ◽  
...  
Keyword(s):  
Quantitative Polymerase Chain Reaction ◽  
Three Dimensional ◽  
Mechanical Force ◽  
Signalling Pathway ◽  
Mechanical Forces ◽  
Matrix Synthesis ◽  
Chain Reaction ◽  
Potential Therapeutic Target ◽  
Polymerase Chain ◽  
The Stability

Abstract The stability of orthodontic treatment is believed to be greatly affected by the compression and contraction of gum tissue, but the underlying molecular mechanism remains unclear. The aim of the current study was to explore the effects of mechanical forces on CRT, CaN, NFAT3, p-NFAT3 and COL-I expression in human gingival fibroblasts (HGFs) cultured on three-dimensional (3D) poly(lactic-co-glycolic acid) (PLGA) scaffolds. A mechanical force of 25 g/cm2 was applied to HGFs for 0, 6, 24, 48, and 72h. The expression of CRT, CaN, NFAT3, p-NFAT3, and COL-I were examined by reverse transcription-quantitative polymerase chain reaction and western blotting analysis. The application of mechanical force on HGFs cultured on the 3D PLGA scaffolds led to a significant increase in CRT, CaN, and COL‑I expression, as well as a reduction in p-NFAT3 expression. The mechanical force effects were reversed by silencing CRT. By lowering the CRT expression, p-NFAT3 was upregulated, while CaN and COL‑I were downregulated in HGFs. These findings suggested that downregulation of CRT inhibited extracellular matrix synthesis, potentially via CaN/NFAT3 signalling pathway. Therefore, CRT may serve as a potential therapeutic target against gingival fibrosis.

scholarly journals A nanobody-based molecular toolkit provides new mechanistic insight into clathrin-coat initiation

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Linton M Traub
Keyword(s):  
Decisive Role ◽  
Subcellular Location ◽  
Combined Approach ◽  
Mechanistic Insight ◽  
Early Endosomes ◽  
The Stability ◽  
And Function ◽  
Insight Into ◽  
Complementarity Determining Region

Besides AP-2 and clathrin triskelia, clathrin coat inception depends on a group of early-arriving proteins including Fcho1/2 and Eps15/R. Using genome-edited cells, we described the role of the unstructured Fcho linker in stable AP-2 membrane deposition. Here, expanding this strategy in combination with a new set of llama nanobodies against EPS15 shows an FCHO1/2–EPS15/R partnership plays a decisive role in coat initiation. A nanobody containing an Asn-Pro-Phe peptide within the complementarity-determining region 3 loop is a function-blocking pseudoligand for tandem EPS15/R EH domains. Yet, in living cells, EH domains gathered at clathrin-coated structures are poorly accessible, indicating residence by endogenous NPF-bearing partners. Forcibly sequestering cytosolic EPS15 in genome-edited cells with nanobodies tethered to early endosomes or mitochondria changes the subcellular location and availability of EPS15. This combined approach has strong effects on clathrin coat structure and function by dictating the stability of AP-2 assemblies at the plasma membrane.

scholarly journals METTL3-Mediated DLGAP1 Antisense RNA 2 Promotes Gastric Cancer Tumorigenesis Through Facilitating C-Myc-Dependent Warburg Effect

2021 ◽  
Author(s):  
Changshun Yang ◽  
Yu Zhang ◽  
Xuefei Cheng ◽  
Weihua Li
Keyword(s):  
Gastric Cancer ◽  
Antisense Rna ◽  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Dependent Manner ◽  
Rna Immunoprecipitation ◽  
The Stability ◽  
A Site ◽  
Rip Assay ◽  
Site Binding

Abstract Background The critical roles of N6-methyladenosine (m6A) modification have been demonstrated by more and more evidence. However, the cross-talking of m6A and long non-coding RNAs (lncRNAs) in gastric cancer (GC) tumorigenesis is still unclear. Here, our work focused on the functions and molecular mechanism of m6A-modified lncRNA DLGAP1 antisense RNA 2 (DLGAP1-AS2) in GC. Methods LncRNA expression profile data was derived from GEO. M6A profile was screened using Methylated RNA immunoprecipitation sequencing (MeRIP-Seq). The metabolism assays were conducted using quantitative analysis of glucose, lactate, ATP and extracellular acidification rate (ECAR). The m6A level of specific RNA was identified using MeRIP-qPCR. The molecular interaction was detected using RIP assay. Results Microarray analysis found that lncRNA DLGAP1-AS2 up-regulated in GC cells. Clinical data showed that DLGAP1-AS2 high-expression was correlated with advanced pathological stage and poor prognosis. Functionally, DLGAP1-AS2 promoted the Warburg effect (aerobic glycolysis) and knockdown of DLGAP1-AS2 suppressed the tumor growth of GC cells. Mechanistically, m6A methyltransferase METTL3 enhanced the stability of DLGAP1-AS2 via m6A site binding. Moreover, DLGAP1-AS2 interacted with YTHDF1 to enhance the stability of c-Myc mRNA through DLGAP1-AS2/m6A/YTHDF1/c-Myc mRNA. Conclusions In conclusion, our work indicates the functions of m6A-modified DLGAP1-AS2 in the GC aerobic glycolysis, disclosing a potential m6A-dependent manner for GC treatment.

scholarly journals Exosomes Derived From Macrophages Enhance Aerobic Glycolysis and Chemoresistance in Lung Cancer by Stabilizing c-Myc via the Inhibition of NEDD4L

2021 ◽  
Vol 8 ◽  
Author(s):  
Huan Wang ◽  
Lie Wang ◽  
Haiyan Pan ◽  
Yaona Wang ◽  
Miao Shi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Aerobic Glycolysis ◽  
Expression Level ◽  
M2 Macrophage ◽  
Potential Therapeutic Target ◽  
Lung Cancers ◽  
Key Factor ◽  
Survival Signaling ◽  
The Stability ◽  
High Expression Level

As one of the most common and lethal cancer, lung cancer severely threatens the health of human. It has been reported that tumor-associated macrophages promote initiation, progression, as well as chemoresistance in human cancers. However, the underneath molecular mechanism that drives chemoresistance in lung cancer is yet not fully characterized. In this article, we demonstrated that M2 macrophage-derived exosomes (MDE) is the key factor to promote cisplatin-resistance in lung cancer. MDE exhibited high expression level of several miRNA including miR-3679-5p. Mechanistically, miR-3679-5p was delivered to lung cancer cells by MDE, downregulating the expression of a known E3 ligase, NEDD4L, which has been identified as a key regulator controlling the stability of c-Myc. Such decreased NEDD4L expression level resulted in the stabilization of c-Myc and elevated glycolysis. The enhanced glycolysis drives the chemoresistance in lung cancer. Taken together, our findings not only show that M2 macrophage induce chemoresistance in lung cancer through MDE mediated miR-3679-5R/NEDD4L/c-Myc signaling cascade, but also shed the light on the mechanism of the cross-talk between M2 macrophage and lung cancers. By pinpointing a potential novel survival signaling pathway, our data could provide a new potential therapeutic target for lung cancer treatment and management.

scholarly journals Serum exosomal miR-451a acts as a candidate marker for pancreatic cancer

2022 ◽  
pp. 172460082110700
Author(s):  
Jia Chen ◽  
Dongting Yao ◽  
Weiqin Chen ◽  
Zhen Li ◽  
Yuanyuan Guo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Diagnostic Marker ◽  
Clinical Stage ◽  
Benign Disease ◽  
Diagnostic Efficiency ◽  
Healthy Individuals ◽  
Serum Samples ◽  
Exosomal Mirnas ◽  
Serum Exosomes

Objectives The aim of this study was to explore the diagnostic efficiency of serum exosomal miR-451a as a novel biomarker for pancreatic cancer. Methods Serum samples were collected prior to treatment. First, we analyzed microRNA (miRNA) profiles in serum exosomes from eight pancreatic cancer patients and eight healthy volunteers. We then validated the usefulness of the selected exosomal miRNAs as biomarkers in another 191 pancreatic cancer patients, 95 pancreatic benign disease (PB) patients, and 90 healthy controls. Results The expression of miR-451a in serum-derived exosomes from pancreatic cancer patients was significantly upregulated compared with those from PB patients and healthy individuals. Serum exosomal miR-451a showed excellent diagnostic power in identifying pancreatic cancer patients. In addition, exosomal miR-451a showed a significant association with clinical stage and distant metastasis in pancreatic cancer, and the expression level of serum exosomal miR-451a was sensitive to therapy and relapse. Conclusions Serum exosomal miR-451a might serve as a novel diagnostic marker for pancreatic cancer.

scholarly journals SGID: a comprehensive and interactive database of the silkworm

Database ◽  
2019 ◽  
Vol 2019 ◽  
Author(s):  
Zhenglin Zhu ◽  
Zhufen Guan ◽  
Gexin Liu ◽  
Yawang Wang ◽  
Ze Zhang
Keyword(s):  
Tertiary Structure ◽  
Subcellular Location ◽  
Biological Data ◽  
Test Results ◽  
Function Annotation ◽  
Interactive Analysis ◽  
Silkworm Genome ◽  
Genome Scale ◽  
Genome Informatics ◽  
High Depth

Abstract Although the domestic silkworm (Bombyx mori) is an important model and economic animal, there is a lack of comprehensive database for this organism. Here, we developed the silkworm genome informatics database (SGID). It aims to bring together all silkworm-related biological data and provide an interactive platform for gene inquiry and analysis. The function annotation in SGID is thorough and covers 98% of the silkworm genes. The annotation details include function description, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway, subcellular location, transmembrane topology, protein secondary/tertiary structure, homologous group and transcription factor. SGID provides genome-scale visualization of population genetics test results based on high-depth resequencing data of 158 silkworm samples. It also provides interactive analysis tools of transcriptomic and epigenomic data from 79 NCBI BioProjects. SGID will be extremely useful to silkworm research in the future.

scholarly journals LncRNA AC245100.4 binds HSP90 to promote the proliferation of prostate cancer

Epigenomics ◽  
2020 ◽  
Vol 12 (15) ◽  
pp. 1257-1271
Author(s):  
Rongjun Cui ◽  
Chi Liu ◽  
Ping Lin ◽  
Hui Xie ◽  
Wei Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Counting ◽  
Chaperone Function ◽  
In Vivo Assays ◽  
Iκb Kinase ◽  
Rna Immunoprecipitation ◽  
The Stability

Aim: To investigate the role and mechanisms of AC245100.4 in prostate cancer. Materials & methods: The expression and location of AC245100.4 were examined using real-time PCR and  in situ hybridization. Cell Counting Kit-8, clone formation, flow cytometry and in vivo assays were conducted to determine the role of AC245100.4. RNA antisense purification with mass spectrometry and RNA immunoprecipitation were performed to identify proteins that bind to AC245100.4. Western blotting was performed to quantify the expression of protein. Results: AC245100.4 expression was upregulated in prostate cancer and mainly located in the cytoplasm. Knockdown of AC245100.4 inhibited proliferation of prostate cancer. Mechanistically, AC245100.4 bound to HSP90 and altered its chaperone function, increased the stability of IκB kinase and activated the NFκB signaling pathway. Conclusion: AC245100.4 promotes the proliferation of prostate cancer via binding of HSP90.

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