Epithelial cell adhesion molecule (EpCAM) is known to be highly expressed in a variety of epithelial carcinomas, and it is involved in cell adhesion and proliferation. However, its expression profile ...and biological function in nasopharyngeal carcinoma (NPC) remains unclear. In this study, higher expression of EpCAM was found in NPC samples compared with non-cancer nasopharyngeal mucosa by qRT-PCR. Additionally, immunohistochemistry (IHC) analysis of NPC specimens from 64 cases showed that high EpCAM expression was associated with metastasis and shorter survival. Multivariate survival analysis identified high EpCAM expression as an independent prognostic factor. Ectopic EpCAM expression in NPC cells promoted epithelial-mesenchymal transition (EMT), induced a cancer stem cell (CSC)-like phenotype, and enhanced metastasis in vitro and in vivo without an effect on cell proliferation. Notably, EpCAM overexpression reduced PTEN expression and increased the level of AKT, mTOR, p70S6K and 4EBP1 phosphorylation. Correspondingly, an AKT inhibitor and rapamycin blocked the effect of EpCAM on NPC cell invasion and stem-like phenotypes, and siRNA targeting PTEN rescued the oncogenic activities in EpCAM knockdown NPC cells. Our data demonstrate that EpCAM regulates EMT, stemness and metastasis of NPC cells via the PTEN/AKT/mTOR pathway.
A nickel‐catalyzed cross‐coupling between (hetero)arylborons and unactivated 1‐bromo‐1,1‐difluoroalkanes has been developed. The use of two ligands (a bidentate bipyridine‐based ligand, ...4,4′‐ditBu‐bpy, and a monodentate pyridine‐based ligand, DMAP) offers a highly efficient nickel‐based catalytic system to prepare difluoroalkylated arenes which have important applications in medicinal chemistry.
Ligand combo: The title reaction requires the use of a combined (2+1) ligand system, that is, a combination of a bi‐ and monodentate ligand (4,4′‐ditBu‐bpy + DMAP). This system allows employment of a wide range of unactivated 1‐bromo‐1,1‐difluoroalkanes as coupling partners, thus providing a highly efficient method for applications in drug discovery and development. bpy=bipyridine, DMAP=4‐(N,N‐dimethylamino)pyridine.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Nasopharyngeal carcinoma (NPC), an Epstein–Barr virus (EBV) associated cancer, exhibits an extremely high incidence in southern Chinese. Given that human leukocyte antigen (HLA) plays ...critical roles in antigen presentation and relates to NPC susceptibility, it is speculated that certain HLA variants may affect EBV reactivation, which is a key pathogenic factor of NPC. Therefore, we attempted to identify HLA alleles associated with the indicator of EBV reactivation, Zta‐IgA, in healthy males from NPC endemic area.
Methods
HLA alleles of 1078 healthy males in southern China from the 21‐RCCP study were imputed using genome‐wide single nucleotide polymorphism data. EBV Zta‐IgA in blood samples were measured using an enzyme‐linked immunosorbent assay. Multiple logistic regression analysis was used to evaluate the effect of HLA allele on Zta‐IgA serological status and its potential joint association with smoking. The binding affinity for Zta‐peptide was predicted using NetMHCIIpan 4.0.
Results
HLA‐DRB1*09:01 was found to be associated with a higher risk of Zta‐IgA seropositivity (odds ratio = 1.80, 95% confidence interval = 1.32–2.45; p = 1.82 × 10−4). Compared with non‐smokers without HLA‐DRB1*09:01, the effect size increased to 2.19‐ and 3.70‐fold for the light and heavy smokers carrying HLA‐DRB1*09:01, respectively. Furthermore, HLA‐DRB1*09:01 showed a stronger binding affinity to Zta peptide than other HLA‐DRB1 alleles.
Conclusions
Our study highlighted the pivotal role of genetic HLA variants in EBV reactivation and the etiology of NPC. Smokers with HLA‐DRB1*09:01 have a significantly higher risk of being Zta‐IgA seropositive, which indicates the necessity of smoking cessation in certain high‐risk populations and also provide clues for further research on the etiology of NPC.
We conducted an association study for human leukocyte antigen (HLA) alleles and Epstein–Barr virus Zta‐IgA serological status in healthy males from a nasopharyngeal carcinoma endemic area. We found that HLA‐DRB1*09:01 was associated with a high risk of Zta‐IgA seropositivity and the effect increased when combined with smoking. In silico prediction indicated that HLA‐DRB1*09:01 had a distinctive binding motif pattern and a stronger binding affinity to Zta peptide in comparison with other HLA‐DRB1 alleles.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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•We promoted a 3D magnetic electrode to prolong the electrocatalytic HER.•In H2-catalyst-III, a PEDOT coating layer can effectively improve HER behavior.•The magnet plays a role in ...strengthening the catalyst’s electron structure.•The optimal H2-catalyst-III electrode exhibits a long lifespan of over 11 days.•A magnetic electrode-based electrolytic cell holds durability for over 10 days.
Most catalysts used for the hydrogen evolution reaction (HER) possess superior electrocatalysis activities but suffer from poor stability, hampering their applications in the electrolysis industry. Here, we fabricated three magnetic electrodes: “H2-catalyst-I” (NiCoFeP@F-NiCoAlFe-LDHs@NiCoFe), “H2-catalyst-II” NiCoFeP@F-NiCoAlFe-LDHs@NiCoFe and NiCoFe), and “H2-catalyst-III” (H2-catalyst-I@poly(3,4-ethylene dioxythiophene) (PEDOT)), to study the effect of magnet field on the electrocatalysis life of NiCo-based phosphides. Among them, the magnetic H2-catalyst-II electrode demonstrates extended stability over 10 days due to the protection effect of NiCoFe alloy powders under a magnetic field, surpassing that of the magnetic H2-catalyst-I electrode. The magnetic H2-catalyst-III electrode exhibits enhanced HER behaviors (η10 = 106 mV, a little Tafel slope of 79 mV·dec-1, and durability for up to 11 days). This stability can be attributed to its strong electron structure nature due to both the magnetic field and the PEDOT coating layer. Finally, an electrolytic cell is assembled by applying the magnetic H2-catalyst-III cathode and F-doped NiCoAl-LDHs@ZnFeAl-LDHs/NF anode and displays the electrocatalysis life over 10 days. In conclusion, the magnetic field holds a beneficial effect on strengthening the electron structure of the catalyst, thereby extending the lifespan of HER, which introduces a new approach for designing and preparing robust HER catalysts to meet the demands in the electrolysis water industry.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•CircVDAC3 is downregulated in gastric cancer.•Overexpression of circVDAC3 inhibits the proliferation and metastasis of gastric cancer cells in vitro and in vivo.•CircVDAC3 is localized in the ...cytoplasm and act as a miR-592 sponge.•CircVDAC3 competitively binds to miR-592 to up-regulate EIF4E3 expression, thereby inhibit the growth and metastasis of gastric cancer cells.
Accumulating evidence has shown that circular RNAs (circRNAs) are involved in gastric cancer (GC) tumorigenesis. However, specific functional circRNAs in GC remain to be discovered, and their underlying mechanisms remain to be elucidated.
CircRNAs that were differentially expressed between GC tissues and controls were analyzed using a circRNA microarray dataset. The expression of circVDAC3 in GC was determined using quantitative real-time PCR (qRT-PCR), and the structural features of circVDAC3 were validated. Cell function assays and animal experiments were conducted to explore the effects of circVDAC3 on GC. Finally, bioinformatics analysis, fluorescent in situ hybridization, and dual luciferase assays were used to analyze the downstream mechanisms of circVDAC3.
Our results showed that circVDAC3 was downregulated in GC and inhibited the proliferation and metastasis of GC cells. Mechanistically, circVDAC3 acts as a competing endogenous RNA (ceRNA) of miR-592 and deregulates the repression of EIF4E3 by miR-592. EIF4E3 is downregulated in GC and overexpression of miR-592 or knockdown of EIF4E3 in circVDAC3-overexpressing cells weakens the anticancer effect of circVDAC3.
Our study provides evidence that circVDAC3 affects the growth and metastasis of GC cells via the circVDAC3/miR-592/EIF4E3 axis. Our findings offer valuable insights into the mechanisms underlying GC tumorigenesis and suggest novel therapeutic strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Increasing evidence suggests that key cancer-causing driver genes continue to exert a sustained influence on the tumor microenvironment (TME), highlighting the importance of immunotherapeutic ...targeting of gene mutations in governing tumor progression.
TP53
is a prominent tumor suppressor that encodes the p53 protein, which controls the initiation and progression of different tumor types. Wild-type p53 maintains cell homeostasis and genomic instability through complex pathways, and mutant p53 (Mut p53) promotes tumor occurrence and development by regulating the TME. To date, it has been wildly considered that
TP53
is able to mediate tumor immune escape. Herein, we summarized the relationship between
TP53
gene and tumors, discussed the mechanism of Mut p53 mediated tumor immune escape, and summarized the progress of applying p53 protein in immunotherapy. This study will provide a basic basis for further exploration of therapeutic strategies targeting p53 protein.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Nasopharyngeal carcinoma (NPC) is closely associated with genetic factors and Epstein-Barr virus infection, showing strong familial aggregation. Individuals with a family history suffer elevated NPC ...risk, requiring effective genetic counseling for risk stratification and individualized prevention.
We performed whole-exome sequencing on 502 familial NPC patients and 404 unaffected relatives and controls. We systematically evaluated the established cancer predisposition genes and investigated novel NPC susceptibility genes, making comparisons with 21 other familial cancers in the UK biobank (N = 5218).
Rare pathogenic mutations in the established cancer predisposition genes were observed in familial NPC patients, including ERCC2 (1.39%), TP63 (1.00%), MUTYH (0.80%), and BRCA1 (0.80%). Additionally, 6 novel susceptibility genes were identified. RAD54L, involved in the DNA repair pathway together with ERCC2, MUTYH, and BRCA1, showed the highest frequency (4.18%) in familial NPC. Enrichment analysis found mutations in TP63 were enriched in familial NPC, and RAD54L and EML2 were enriched in both NPC and other Epstein-Barr virus-associated cancers. Besides rare variants, common variants reported in the studies of sporadic NPC were also associated with familial NPC risk. Individuals in the top quantile of common variant-derived genetic risk score while carrying rare variants exhibited increased NPC risk (odds ratio = 13.47, 95% confidence interval = 6.33 to 28.68, P = 1.48 × 10-11); men in this risk group showed a cumulative lifetime risk of 24.19%, much higher than those in the bottom common variant-derived genetic risk score quantile and without rare variants (2.04%).
This study expands the catalog of NPC susceptibility genes and provides the potential for risk stratification of individuals with an NPC family history.
•ATPR induced SKM-1 cells differentiation and inhibited its proliferation.•DDX23 played a crucial role in SKM-1 cell development.•DDX23 was involved in the action of ATPR on SKM-1 cells.
...Myelodysplastic syndrome (MDS) is a heterogeneously cloned hematopoietic stem cell malignancy with a high risk of developing acute myeloid leukemia (AML). 4-amino-2-trifluoromethyl-phenyl resinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed in our group, was proved to be a tumor inhibitor in diverse types of cancer cells in vitro. However, little has been known about the effects of ATPR on MDS. To analyze if and to what extent it's anti-tumor activity on MDS, we performed CCK-8, Flow Cytometry, Wright-Giemsa staining, qRT-PCR, and Western blot to analyze the SKM-1 cells state after ATPR treatment in multiplex detection angles. As expected, our results proved that ATPR could effectively induce cell differentiation and reduce cell proliferation of SKM-1 cell lines. Subsequently, to further analyze the potential mechanisms, we applied Label-free proteomic techniques to discover relevant protein that may be involved. Most notably, a series of factors related to RNA behavioral regulation were changed. Among them, we demonstrated that DEAD-box RNA helicase DDX23 was abnormally ablated in MDS patients and could be restored after ATPR treatment in vitro. Besides, our results suggested that ATPR-induced SKM-1 cell maturation was counteracted when knockdown DDX23, underscoring that DDX23 might be involved. In conclusion, we confirmed that ATPR could induce SKM-1 cells differentiation and its positive influence of DDX23 may provide a new idea to relieve MDS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
MicroRNAs, as small non-coding RNAs, play an important role in tumorigenesis. MiR-483-5p was found to have a significant increase as a diagnostic biomarker of nasopharyngeal carcinoma (NPC), not only ...in plasma from NPC patients but also in tumor cell lines and biopsy tissues in our previous study. However, its function and mechanism in NPC are still unclear.
Tissue microarray including 178 primary NPC and 35 adjacent non-cancerous nasopharyngeal mucosal tissues was used to further validate the overexpression of miR-483-5p. Wound healing and invasion assays were conducted to verify its biological function. RNA sequencing (RNA-seq) and dual-luciferase reporter assay was performed to explore its target, and it was verified in fresh biopsy tissues from 23 NPC patients and 9 patients with chronic nasopharyngitis.
MiR-483-5p was highly expressed in NPC tissues than in adjacent non-cancerous tissues. It was found to have a significant correlation with poor overall survival (OS) hazard ratio (HR) = 2.89, 95% confidence interval (CI) = 1.00-8.35,
= 0.041 and progression-free survival (PFS) (HR = 1.95, 95%CI = 1.06-3.60,
= 0.029) of NPC patients. Silencing of its expression inhibited the migratory and invasive capacities of NPC cells
.
(early growth response 3) was identified as a direct target, and inhibiting miR-483-5p expression markedly enhanced the expression of
at both the mRNA and protein levels. Besides, a significant decrease of
expression was found in fresh biopsy tissues from NPC patients, in contrast to miR-483-5p expression. Furthermore, directly decreasing the expression of
could enhance the migration and invasion of NPC cells.
The newly identified miR-483-5p/
pathway provides further insights into the development and metastasis of NPC and may provide a potential therapeutic target for NPC treatment in order to improve survival of NPC patients.
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