The oncogene c‐Myc is aberrantly expressed and plays a key role in malignant transformation and progression of hepatocellular carcinoma (HCC). Here, we report that c‐Myc is significantly up‐regulated ...by tumor necrosis factor receptor–associated factor 6 (TRAF6), an E3 ubiquitin ligase, in hepatocarcinogenesis. High TRAF6 expression in clinical HCC samples correlates with poor prognosis, and the loss of one copy of the Traf6 gene in Traf6+/– mice significantly impairs liver tumorigenesis. Mechanistically, TRAF6 first interacts with and ubiquitinates histone deacetylase 3 (HDAC3) with K63‐linked ubiquitin chains, which leads to the dissociation of HDAC3 from the c‐Myc promoter and subsequent acetylation of histone H3 at K9, thereby epigenetically enhancing the mRNA expression of c‐Myc. Second, the K63‐linked ubiquitination of HDAC3 impairs the HDAC3 interaction with c‐Myc and promotes c‐Myc protein acetylation, which thereby enhances c‐Myc protein stability by inhibiting carboxyl terminus of heat shock cognate 70‐kDa–interacting protein–mediated c‐Myc ubiquitination and degradation. Importantly, TRAF6/HDAC3/c‐Myc signaling is also primed in hepatitis B virus–transgenic mice, unveiling a critical role for a mechanism in inflammation–cancer transition. In clinical specimens, TRAF6 positively correlates with c‐Myc at both the mRNA and protein levels, and high TRAF6 and c‐Myc expression is associated with an unfavorable prognosis, suggesting that TRAF6 collaborates with c‐Myc to promote human hepatocarcinogenesis. Consistently, curbing c‐Myc expression by inhibition of TRAF6 activity with a TRAF6 inhibitor peptide or the silencing of c‐Myc by small interfering RNA significantly suppressed tumor growth in mice. Conclusion: These findings demonstrate the oncogenic potential of TRAF6 during hepatocarcinogenesis by modulating TRAF6/HDAC3/c‐Myc signaling, with potential implications for HCC therapy.
Abstract
Background
Adding radiotherapy (RT) to systemic therapy improves progression-free survival (PFS) and overall survival (OS) in oligometastatic non-small cell lung cancer (NSCLC). Whether ...these findings translate to epidermal growth factor receptor (EGFR)–mutated NSCLC remains unknown. The SINDAS trial (NCT02893332) evaluated first-line tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated synchronous oligometastatic NSCLC and randomized to upfront RT vs no RT; we now report the prespecified interim analysis at 68% accrual.
Methods
Inclusion criteria were biopsy-proven EGFR-mutated adenocarcinoma (per amplification refractory mutation system or next generation sequencing), with synchronous (newly diagnosed, treatment naïve) oligometastatic (≤5 metastases; ≤2 lesions in any one organ) NSCLC without brain metastases. All patients received a first-generation TKI (gefitinib, erlotinib, or icotinib), and randomization was between no RT vs RT (25-40 Gy in 5 fractions depending on tumor size and location) to all metastases and the primary tumor/involved regional lymphatics. The primary endpoint (intention to treat) was PFS. Secondary endpoints included OS and toxicities. All statistical tests were 2-sided.
Results
A total of 133 patients (n = 65 TKI only, n = 68 TKI with RT) were enrolled (2016-2019). The median follow-up was 23.6 months. The respective median PFS was 12.5 months vs 20.2 months (P < .001), and the median OS was 17.4 months vs 25.5 months (P < .001) for TKI only vs TKI with RT. Treatment yielded no grade 5 events and a 6% rate of symptomatic grade 3-4 pneumonitis in the TKI with RT arm. Based on the efficacy results of this prespecified interim analysis, the ethics committee recommended premature cessation of this trial.
Conclusions
As compared with a first-line TKI alone, addition of upfront local therapy using RT statistically significantly improved PFS and OS for EGFR-mutated NSCLC.
MicroRNA-124 (miR-124) is the most abundant miRNA in the brain. Biogenesis of miR-124 displays specific temporal and spatial profiles in various cell and tissue types and affects a broad spectrum of ...biological functions in the central nervous system (CNS). Recently, the link between dysregulation of miR-124 and CNS disorders, such as neurodegeneration, CNS stress, neuroimmune disorders, stroke, and brain tumors, has become evident. Here, we provide an overview of the specific molecular function of miR-124 in the CNS and a revealing insight for the therapeutic potential of miR-124 in the treatment of human CNS diseases.
The class III deacetylase sirtuin 1 (SIRT1), a member of the sirtuin family proteins, plays a key role in many types of cancers including colorectal cancer (CRC). Here we report that SIRT1 suppressed ...CRC metastasis in vitro and in vivo as a negative regulator for miR-15b-5p transcription. Mechanistically, SIRT1 impaired regulatory effects of activator protein (AP-1) on miR-15b-5p trans-activation through deacetylation of AP-1. Importantly, acyl-CoA oxidase 1 (ACOX1), a key enzyme of the fatty acid oxidation (FAO) pathway, was found as a direct target for miR-15b-5p. SIRT1 expression was positively correlated with ACOX1 expression in CRC cells and in xenografts. Moreover, ACOX1 overexpression attenuated the augmentation of migration and invasion of CRC cells by miR-15b-5p overexpression. In conclusion, our study demonstrated a functional role of the SIRT1/miR-15b-5p/ACOX1 axis in CRC metastasis and suggested a potential target for metastatic CRC therapy.
•SIRT1 is a tumor suppressor gene in colorectal cancer patients.•SIRT1 suppresses CRC metastasis by blocking miR-15b-5p transcription.•SIRT1 suppresses miR-15b-5p transcription by impairing the binding of AP-1 to its promoter.•SIRT1 inhibits CRC metastasis through SIRT1/miR-15b-5p/ACOX1 axis.
Activated carbon is commonly used to remove dioxins from flue gas via adsorption. Improving the targeted adsorption capacity of activated carbon for dioxins can reduce the consumption of adsorbents ...and help achieve emission standards for target pollutants. Here, commercial coal-based activated carbon was used as a raw material and modified by urea impregnation along with treatment at high temperature under a nitrogen atmosphere. It was found that modification with urea effectively improved the pore structure of activated carbon while incorporating a certain amount of nitrogen. The best modification effect was achieved at a modification temperature of 600 °C, an impregnation ratio of urea to activated carbon of 1:1, and with high-temperature treatment for 2 h. The mesopore volume of the modified activated carbon (AC600) reached 0.38 cm3/g, accounting for 57.58% of the total pore volume. With an impregnation ratio of urea to activated carbon of 1:1, high-temperature treatment for 2 h, and a modification temperature of 800 °C, a certain amount of nitrogen was introduced into the carbon rings to form a modified activated carbon (AC800) rich in pyridine and pyrrole groups (atomic percentage = 4.84%). The activated carbon modified by urea and the unmodified activated carbon were subsequently selected for dioxin adsorption experiments using a dioxin generation and adsorption system. AC600 showed the highest adsorption efficiency for dioxins, reaching 97.65%, based on toxicity equivalents. Although AC800 has poor pore properties, it has more pyridine and pyrrole groups than AC600. Consequently, the efficiency of AC800 at adsorbing low-concentration dioxins reached 85.24% based on toxicity equivalents. Overall, this study describes two mechanisms for effectively modifying activated carbon with urea based on (1) optimizing the pore structure of activated carbon and (2) incorporating nitrogen.
•The pore structure of urea-modified activated carbon was more suitable for PCDD/F adsorption.•Higher modified temperature was prone to form more pyridine and pyrrole groups.•The adsorption behavior of PCDD/Fs by urea-modified activated carbon were systematically investigated.
A limit to the clinical benefit of radiotherapy is not an incapacity to eliminate tumor cells but rather a limit on its capacity to do so without destroying normal tissue and inducing inflammation. ...Recent evidence reveals that the inflammasome is essential for mediating radiation-induced cell and tissue damage. In this study, using primary cultured bone marrow-derived macrophages (BMDM) and a mouse radiation model, we explored the role of NLRP3 inflammasome activation and the secondary pyroptosis underlying radiation-induced immune cell death. We observed an increasing proportion of pyroptosis and elevating Caspase-1 activation in 10 and 20 Gy radiation groups. Nlrp3 knock out significantly diminished the quantity of cleaved-Caspase-1 (p10) and IL-1β as well as the proportion of pyroptosis. Additionally, in vivo research shows that 9.5 Gy of radiation promotes Caspase-1 activation in marginal zone cells and induces death in mice, both of which can be significantly inhibited by knocking out Nlrp3. Thus, based on these findings, we conclude that the NLRP3 inflammasome activation mediates radiation-induced pyroptosis in BMDMs. Targeting NLRP3 inflammasome and pyroptosis may serve as effective strategies to diminish injury caused by radiation.
F− detection: Two new polydentate conjugate molecules (1 and 2) as colorimetric receptors for detecting F− have been synthesized and found to have high fluorescent selectivity for detecting F−. In ...particular, receptor 1 has a more rigid structure without conformational flexibity that can be used as a ratiometric receptor of F−.
A polypyridyl ligand, 2,3,6,7,10,11-hexakis(2-pyridyl)dipyrazino2,3-f:2′,3′-hquinoxaline (HPDQ), was found to have excellent fluorescent selectivity for Cd2+ over many other metal ions (K+, Na+, ...Ca2+, Mg2+, Mn2+, Fe2+, Ni2+, Co2+, Cu2+, Ag+, Hg2+, Zn2+, and Cr3+) based on the intramolecular charge-transfer mechanism, which makes HPDQ a potential fluorescence sensor or probe for Cd2+. An obvious color change between HPDQ and HPDQ + Cd2+ can be visually observed by the naked eye. The structure of the complex HPDQ-Cd has been characterized by X-ray crystallography. Density functional theory calculation results on the HPDQ and HPDQ-Cd complexes could explain the experimental results.
In higher plants, DREB1/CBF-type transcription factors play an important role in tolerance to low temperatures, drought, and high-salt stress. These transcription factors bind to CRT/DRE elements in ...promoter regions of target genes, regulating their expression. In this study, we cloned and characterized a novel gene encoding a DREB1 transcription factor from dwarf apple, Malus baccata (GenBank accession number: EF582842). Expression of MbDREB1 was induced by cold, drought, and salt stress, and also in response to exogenous ABA. Subcellular localization analyses revealed that MbDREB1 localizes in the nucleus. A yeast activity assay demonstrated that the MbDREB1 gene encodes a transcription activator, which specifically binds to DRE/CRT elements. Compared with wild-type plants, transgenic Arabidopsis overexpressing MbDREB1 showed increased tolerance to low temperature, drought, and salt stresses. Analysis of the MbDREB1 promoter revealed an ABA-responsive element (ABRE), an inducer of CBF expression 1 (ICE1)-like binding site, two MYB recognition sites, and three stress-inducible GT-1 boxes. GUS activities driven by the MbDREB1 promoter in transgenic Arabidopsis increased in response to ABA, cold temperature, drought, and salt treatments. Interestingly, the expression of both ABA-independent and ABA-dependent stress-induced genes (COR15a and rd29B, respectively) was activated under normal growth conditions in Arabidopsis overexpressing MbDREB1. These results suggest that MbDREB1 functions as a transcription factor and increases plant tolerance to low temperature, drought, and salt stress via both ABA-dependent and ABA-independent pathways.
Retinal ganglion cell (RGC) injury is one of the important pathological features of diabetes-induced retinal neurodegeneration. Increasing attention has been paid to find strategies for protecting ...against RGC injury. Long noncoding RNAs (lncRNAs) have emerged as the key regulators of many cell functions. Here, we show that Sox2OT expression is significantly down-regulated in the retinas of STZ-induced diabetic mice and in the RGCs upon high glucose or oxidative stress. SOX2OT knockdown protects RGCs against high glucose-induced injury in vitro. Moreover, Sox2OT knockdown plays a neuroprotective role in diabetes-related retinal neurodegeneration in vivo. Sox2OT knockdown could regulate oxidative stress response in RGCs and diabetic mouse retinas. Sox2OT knockdown plays an anti-oxidative role via regulating NRF2/HO-1 signaling activity. Taken together, Sox2OT knockdown may be a therapeutic strategy for the prevention and treatment of diabetes-induced retinal neurodegeneration.
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