Abstract
Background
Circular RNA (circRNAs) and hypoxia have been found to play the key roles in the pathogenesis and progression of cancer including colorectal cancer (CRC). However, the expressions ...and functions of the specific circRNAs in regulating hypoxia-involved CRC metastasis, and the circRNAs that are relevant to regulate HIF-1α levels in CRC remain elusive.
Methods
qRT-PCR was used to detect the expression of circRNAs and mRNA in CRC cells and tissues. Fluorescence in situ hybridization (FISH) was used to analyze the location of circ-ERBIN. Function-based experiments were performed using circ-ERBIN overexpression and knockdown cell lines in vitro and in vivo, including CCK8, colony formation, EdU assay, transwell, tumor growth and metastasis models. Mechanistically, luciferase reporter assay, western blots and immunohistochemical stainings were performed.
Results
Circ-Erbin was highly expressed in the CRC cells and Circ-Erbin overexpression facilitated the proliferation, migration and metastasis of CRC in vitro and in vivo. Notably, circ-Erbin overexpression significantly promoted angiogenesis by increasing the expression of hypoxia induced factor (HIF-1α) in CRC. Mechanistically, circ-Erbin accelerated a cap-independent protein translation of HIF-1α in CRC cells as the sponges of miR-125a-5p and miR-138-5p, which synergistically targeted eukaryotic translation initiation factor 4E binding protein 1(4EBP-1).
Conclusions
Our findings uncover a key mechanism for circ-Erbin mediated HIF-1α activation by miR-125a-5p-5p/miR-138-5p/4EBP-1 axis and circ-ERBIN is a potential target for CRC treatment.
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.
The grain structure of the selective laser melting additive manufactured parts has been shown to be heterogeneous and spatially non-uniform compared to the traditional manufacturing process. However, ...the complex formation mechanism of these unique grain structures is hard to reveal using the experimental method alone. In this study, we presented a high-fidelity 3D numerical model to address the grain growth mechanisms during the selective laser melting of 316 stainless steel, including two heating modes, i.e., conduction mode and keyhole mode melting. In the numerical model, the powder-scale thermo-fluid dynamics are simulated using the finite volume method with the volume of fluid method. At the same time, the grain structure evolution is sequentially predicted by the cellular automaton method with the predicted temperature field and the as-melted powder bed configuration as input. The simulation results agree well with the experimental data available in the literature. The influence of the process parameters and the keyhole and keyhole-induced void on grain structure formation are addressed in detail. The findings of this study are helpful to the optimization of process parameters for tailoring the microstructure of fabricated parts with expected mechanical properties.
Baicalein (BAI), one of the main components of
, possesses numerous pharmacological properties, including anti-cancer, anti-oxidative, anti-virus and anti-bacterial activities. The purpose of this ...study was to evaluate the hepatoprotective effect of baicalein against acetaminophen (APAP)-exposed liver injury in mice, and elucidate the underlying hepatoprotective mechanism. Baicalein pretreatment significantly alleviated the elevation of IL-6, IL-1β and TNF-α in serum and hepatic in a dose-dependent manner. It also dose-dependently reduced the hepatic malondialdehyde (MDA) concentration, as well as the depletion of hepatic superoxide dismutase (SOD), hepatic glutathione (GSH) and hepatic catalase (CAT). Moreover, pretreatment with baicalein significantly ameliorated APAP-exposed liver damage and histological hepatocyte changes. Baicalein also relieved APAP-induced autophagy by regulating AKT/mTOR pathway, LC3B and P62 expression. Furthermore, the hepatoprotective effect of baicalein to APAP-induced liver injury involved in Jak2/Stat3 and MAPK signaling pathway. Taken together, our findings suggested that baicalein exhibits the ability to prevent liver from APAP-induced liver injury and provided an underlying molecular basis for potential applications of baicalein to cure liver injuries.
Compared to monometallic counterparts, bimetallic two‐dimensional conjugated metal‐organic framework (2D c‐MOF) nanosheets possess preferable metal tunability and synergistic effect for performance ...optimization, yet rarely developed in photocatalytic hydrogen evolution to date. In this study, a feasible post‐synthetic strategy of second metal installation (SMI) is proposed and applied to construct a crystalline bimetallic 2D c‐MOF nanosheet, HTHATN‐Ni‐Pt‐NS. HTHATN‐Ni‐Pt‐NS exhibits high electrical conductivity and efficient hydrogen evolution with the rate of 47.2 mmol g−1 h−1, which is 13.5‐fold higher than that of pristine HTHATN‐Ni‐NS without PtII decoration under visible light irradiation. Experimental and theoretical analysis reveal that introduction of low amount of PtII provides catalytically active metal sites and optimizes the ΔGH* value of NiII centers, thus resulting in the enhanced performance of proton reduction. This study represents the first example of symbiotic bimetallic centers in MOF nanosheets highlighting SMI strategy as an efficient approach to construct photocatalysts.
Post‐synthetic strategy of second metal installation is feasible to construct bimetallic metal‐organic framework nanosheet for synergetic photocatalytic hydrogen evolution. PtII as the second metal is coordinated to remained −C2N− unit of Ni‐based 2D conjugated network, optimizing ΔGH* value, serving as preferential active site and endowing NiII site with efficient activity of proton reduction.
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.
The Bangong‐Nujiang Suture Zone (BNSZ) in central Tibet represents relics of the Meso‐Tethys Ocean that once separated the Lhasa and Qiangtang terranes. When and how this ocean closed has been a ...matter of debate, and the cause of the uncertainty stems primarily from a lack of consensus as to whether Early Cretaceous ophiolite exists within the BNSZ. New geochronological and geochemical data presented here identify ∼138–134 Ma MORB‐like and OIB‐type mafic rocks in the Kangqiong area of the western BNSZ. These data, together with the spatially associated peridotite and marine sediment, provide the first firm evidence for the presence of Early Cretaceous ophiolite within the BNSZ. Our integrated study of geological, mineralogical, and geochemical data suggests that the Kangqiong Ophiolite formed in a forearc setting related to the subduction re‐initiation of the Meso‐Tethys Ocean. By combining the present results with a synthesis of tectonomagmatism in central Tibet, including the existence of an Early Jurassic oceanic plateau within the Meso‐Tethys Ocean, the magmatic lull (∼145–130 Ma) in the Qiangtang Terrane, an angular unconformity between Lower Jurassic oceanic rocks and Upper Jurassic shallow‐marine strata, and the compositional differences and migration of magmatism before and after the magmatic lull, we propose a new model of the evolution of the Meso‐Tethys Ocean. This model proposes that the collision of an oceanic plateau with the Qiangtang continental margin caused the termination of Meso‐Tethyan subduction during the Late Jurassic and subsequent re‐initiation behind the oceanic plateau during the Early Cretaceous.
Key Points
First evidence for the presence of Early Cretaceous ophiolite within the Bangong‐Nujiang Suture Zone, central Tibet
The Kangqiong Ophiolite formed in a fore‐arc setting that was synchronous with a magmatic lull following a collisional event
Subduction termination and re‐initiation of Meso‐Tethys Ocean caused by collision of an oceanic plateau with Qiangtang continental margin
Ubiquitination is a basic post-translational modification for cellular homeostasis, and members of the conjugating enzyme (E2) family are the key components of the ubiquitin-proteasome system. ...However, the role of E2 family in colorectal cancer (CRC) is largely unknown. Our study aimed to investigate the role of Ube2v1, one of the ubiquitin-conjugating E2 enzyme variant proteins (Ube2v) but without the conserved cysteine residue required for the catalytic activity of E2s, in CRC.
Immunohistochemistry and real-time RT-PCR were used to study the expressions of Ube2v1 at protein and mRNA levels in CRC, respectively. Western blotting and immunofluorescence, transmission electron microscopy, and in vivo rescue experiments were used to study the functional effects of Ube2v1 on autophagy and EMT program. Quantitative mass spectrometry, immunoprecipitation, ubiquitination assay, western blotting, and real-time RT-PCR were used to analyze the effects of Ube2v1 on histone H4 lysine 16 acetylation, interaction with Sirt1, ubiquitination of Sirt1, and autophagy-related gene expression.
Ube2v1 was elevated in CRC samples, and its increased expression was correlated with poorer survival of CRC patients. Ube2v1 promoted migration and invasion of CRC cells in vitro and tumor growth and metastasis of CRC cells in vivo. Interestingly, Ube2v1suppressed autophagy program and promoted epithelial mesenchymal transition (EMT) and metastasis of CRC cells in an autophagy-dependent pattern in vitro and in vivo. Moreover, both rapamycin and trehalose attenuated the enhanced Ube2v1-mediated lung metastasis by inducing the autophagy pathway in an orthotropic mouse xenograft model of lung metastasis. Mechanistically, Ube2v1 promoted Ubc13-mediated ubiquitination and degradation of Sirt1 and inhibited histone H4 lysine 16 acetylation, and finally epigenetically suppressed autophagy gene expression in CRC.
Our study functionally links Ube2v1, an E2 member in the ubiquitin-proteasome system, to autophagy program, thereby shedding light on developing Ube2v1 targeted therapy for CRC patients.
Antagonist peptides (ANTs) of vasoactive intestinal polypeptide receptors (VIP-Rs) are shown to enhance T cell activation and proliferation in vitro, as well as improving T cell-dependent anti-tumor ...response in acute myeloid leukemia (AML) murine models. However, peptide therapeutics often suffer from poor metabolic stability and exhibit a short half-life/fast elimination in vivo. In this study, we describe efforts to enhance the drug properties of ANTs via chemical modifications. The lead antagonist (ANT308) is derivatized with the following modifications: N-terminus acetylation, peptide stapling, and PEGylation. Acetylated ANT308 exhibits diminished T cell activation in vitro, indicating that N-terminus conservation is critical for antagonist activity. The replacement of residues 13 and 17 with cysteine to accommodate a chemical staple results in diminished survival using the modified peptide to treat mice with AML. However, the incorporation of the constraint increases survival and reduces tumor burden relative to its unstapled counterpart. Notably, PEGylation has a significant positive effect, with fewer doses of PEGylated ANT308 needed to achieve comparable overall survival and tumor burden in leukemic mice dosed with the parenteral ANT308 peptide, suggesting that polyethylene glycol (PEG) incorporation enhances longevity, and thus the antagonist activity of ANT308.
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