• Hansson Kyed posted an update 6 months, 3 weeks ago

    NF-κB inhibitor, BAY 11-7082, suppressed decitabine-induced CD4

    T cell proliferation and IFN-γ production. In terms of mechanism, low-dose decitabine augmented the expression of E3 ligase β-TrCP, promoted the ubiquitination and degradation of IκBα and resulted in NF-κB activation. Notably, we observed that

    low-dose decitabine treatment induced NF-κB activation in CD4

    T cells from patients with a response to decitabine-primed chemotherapy rather than those without a response.

    These data suggest that low-dose decitabine potentiates CD4

    T cell anti-tumor immunity through enhancing IκBα degradation and therefore NF-κB activation and IFN-γ production.

    These data suggest that low-dose decitabine potentiates CD4+ T cell anti-tumor immunity through enhancing IκBα degradation and therefore NF-κB activation and IFN-γ production.

    N

    -methyladenosine (m

    A) RNA methylation is implicated in the progression of multiple cancers via influencing mRNA modification. YTHDF1 can act as an oncogene in gastric cancer (GC), while the biological mechanisms via which YTHDF1 regulates gastric tumorigenesis through m

    A modification remain largely unknown.

    GEO and TCGA cohorts were analyzed for differentially expressed m

    A modification components in GC clinical specimens and their association with clinical prognosis. Transwell and flow cytometry assays as well as subcutaneous xenograft and lung metastasis models were used to evaluate the phenotype of YTHDF1 in GC. Intersection of RNA/MeRIP-seq, luciferase assay, RIP-PCR, RNA pull-down and MeRIP-PCR was used to identify YTHDF1- modified USP14 and its m

    A levels in GC cells.

    High-expressed YTHDF1 was found in GC tissues and was related to poor prognosis, acting as an independent prognostic factor of poor survival in GC patients. YTHDF1 deficiency inhibited cell proliferation and invasion (

    ), and gastric tumorigenesis and lung metastasis (

    ) and also induced cell apoptosis. Intersection assays revealed that YTHDF1 promoted USP14 protein translation in an m

    A-dependent manner. USP14 upregulation was positively correlated with YTHDF1 expression and indicated a poor prognosis in GC.

    Our data suggested that m

    A reader YTHDF1 facilitated tumorigenesis and metastasis of GC by promoting USP14 protein translation in an m

    A-dependent manner and might provide a potential target for GC treatment.

    Our data suggested that m6A reader YTHDF1 facilitated tumorigenesis and metastasis of GC by promoting USP14 protein translation in an m6A-dependent manner and might provide a potential target for GC treatment.Triple-negative breast cancer (TNBC) has high malignancy and limited treatment, so novel molecular therapeutic targets are urgently needed. Cyclin E1 (CCNE1) promotes progression in breast cancer, but its role and inherent mechanisms in TNBC are yet to be elucidated. Competing endogenous RNA (ceRNA) may be a potential mechanism. CCNE1 was selected though bioinformatics and clinical samples, and cell lines were utilized to verify CCNE1 expression by qRT-PCR and western blot. #link# Predicting Luminespib in vitro provided potential miR-195-5p and SENP3-EIF4A1 and tested from multilevel. Functional experiments were conducted in vitro and in vivo. Luciferase reporter assay and RNA immunoprecipitation experiments were implemented to ensure the interaction between miR-195-5p and SENP3-EIF4A1/CCNE1 in TNBC. Bioinformatics found DNA hypermethylation of miR-195-5p and preliminarily verified. Mechanistically, SENP3-EIF4A1-miR-195-5p-associated ceRNA could drive TNBC progress though regulating CCNE1. DNA hypermethylation of miR-195-5p might be another reason. In summary, SENP3-EIF4A1-miR-195-5p-CCNE1 axis promotes TNBC progress and may contribute to the novel diagnosis and treatment of TNBC.Hepatocellular carcinoma (HCC) is one of the malignant tumors with poor prognosis. High expression level of cofilin 1 (CFL1) has been found in many types of cancers. However, the role of CFL1 in HCC hasn’t been known clearly. Here, we found that CFL1 was up regulated in human HCC and significantly associated with both overall survival and disease-free survival in HCC patients. Nujiangexanthone A (NJXA), the caged xanthones, isolated from gamboge plants decreased the expression of CFL1, which also inhibited the migration, invasion and metastasis of HCC cells in vitro and in vivo. Down regulation of CFL1 inhibited aggressiveness of HCC cells, which mimicked the effect of NJXA. Mechanism study indicated that, knockdown of CFL1 or treatment with NJXA increased the level of F-actin and disturbed the balance between F-actin and G-actin. In conclusion, our findings reveal the role of CFL1 in HCC metastasis through the CFL1/F-actin axis, and suggest that CFL1 may be a potential prognostic marker and a new therapeutic target. NJXA can effectively inhibit the metastasis of HCC cells by down regulating the expression of CFL1, which indicates the potential of NJXA for preventing metastasis in HCC.The etiology of non-alcoholic fatty liver disease (NAFLD) involves complex interaction of genetic and environmental factors. A large number of observational studies have shown that hypothyroidism contributes to a high risk of NAFLD. However, the exact causality is still unknown. Due to the progress of genome-wide association study (GWAS) and the discovery of Mendelian randomization (MR), it is possible to explore the causality between the two diseases. In this study, in order to research into the influence of intermediate phenotypes on outcome, nine independent genetic variants of hypothyroidism obtained from the GWAS were used as instrumental variables (IVs) to perform MR analysis on NAFLD. Since there was no heterogeneity between IVs (P = 0.70), a fixed-effects model was used. The correlation between hypothyroidism and NAFLD was evaluated by using inverse-variance weighted (IVW) method and weighted median method. Then the sensitivity test was analyzed. The results showed that there was a high OR (1.7578; 95%CI 1.1897-2.5970; P = 0.0046) and a low intercept (-0.095; P = 0.431). None of the genetic variants drove the overall result (P less then 0.01). Simply, we proved for the first time that the risk of NAFLD increases significantly on patients with hypothyroidism. Furthermore, we explained possible causes of NAFLD caused by hypothyroidism.

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