Circular RNAs (circRNAs) have been reported to have critical regulatory roles in tumor biology. However, their contribution to melanoma remains largely unknown.
CircRNAs derived from oncogene CD151 ...were detected and verified by analyzing a large number of melanoma samples through quantitative real-time polymerase chain reaction (qRT-PCR). Melanoma cells were stably transfected with lentiviruses using circ_0020710 interference or overexpression plasmid, and then CCK-8, colony formation, wound healing, transwell invasion assays, and mouse xenograft models were employed to assess the potential role of circ_0020710. RNA immunoprecipitation, luciferase reporter assay and fluorescence in situ hybridization were used to evaluate the underlying mechanism of circ_0020710.
Our findings indicated that circ_0020710 was generally overexpressed in melanoma tissues, and high level of circ_0020710 was positively correlated with malignant phenotype and poor prognosis of melanoma patients. Elevated circ_0020710 promoted melanoma cell proliferation, migration and invasion in vitro as well as tumor growth in vivo. Mechanistically, we found that high level of circ_0020710 could upregulate the CXCL12 expression via sponging miR-370-3p. CXCL12 downregulation could reverse the malignant behavior of melanoma cells conferred by circ_0020710 over expression. Moreover, we also found that elevated circ_0020710 was correlated with cytotoxic lymphocyte exhaustion, and a combination of AMD3100 (the CXCL12/CXCR4 axis inhibitor) and anti-PD-1 significantly attenuated tumor growth.
Elevated circ_0020710 drives tumor progression via the miR-370-3p/CXCL12 axis, and circ_0020710 is a potential target for melanoma treatment.
Although recent therapeutic advances based on our understanding of molecular phenomena have prolonged the survival of melanoma patients, the prognosis of melanoma remains dismal and further ...understanding of the underlying mechanism of melanoma progression is needed. In this study, differential expression analyses revealed that many genes, including AKT1 and CDK2, play important roles in melanoma. Functional analyses of differentially expressed genes (DEGs), obtained from the GEO (Gene Expression Omnibus) database, indicated that high proliferative and metastatic abilities are the main characteristics of melanoma and that the PI3K and MAPK pathways play essential roles in melanoma progression. Among these DEGs, major facilitator superfamily domain-containing 12 (MFSD12) was found to have significantly and specifically upregulated expression in melanoma, and elevated MFSD12 level promoted cell proliferation by promoting cell cycle progression. Mechanistically, MFSD12 upregulation was found to activate PI3K signaling, and a PI3K inhibitor reversed the increase in cell proliferation endowed by MFSD12 upregulation. Clinically, high MFSD12 expression was positively associated with shorter overall survival (OS) and disease-free survival (DFS) in melanoma patients, and MFSD12 was an independent prognostic factor for OS and DFS in melanoma patients. Therapeutically, in vivo assays further confirmed that MFSD12 interference inhibited tumor growth and lung metastasis in melanoma. In conclusion, elevated MFSD12 expression promotes melanoma cell proliferation, and MFSD12 is a valuable prognostic biomarker and promising therapeutic target in melanoma.
ABSTRACT
Lignin is a major component of plant cell walls and is essential for plant growth and development. Lignin biosynthesis is controlled by a hierarchical regulatory network involving multiple ...transcription factors. In this study, we showed that the gene encoding an APETALA 2/ethylene‐responsive element binding factor (AP2/ERF) transcription factor, PagERF81, from poplar 84 K (Populus alba × P. glandulosa) is highly expressed in expanding secondary xylem cells. Two independent homozygous Pagerf81 mutant lines created by gene editing, produced significantly more but smaller vessel cells and longer fiber cells with more lignin in cell walls, while PagERF81 overexpression lines had less lignin, compared to non‐transgenic controls. Transcriptome and reverse transcription quantitative PCR data revealed that multiple lignin biosynthesis genes including Cinnamoyl CoA reductase 1 (PagCCR1), Cinnamyl alcohol dehydrogenase 6 (PagCAD6), and 4‐Coumarate‐CoA ligase‐like 9 (Pag4CLL9) were up‐regulated in Pagerf81 mutants, but down‐regulated in PagERF81 overexpression lines. In addition, a transient transactivation assay revealed that PagERF81 repressed the transcription of these three genes. Furthermore, yeast one hybrid and electrophoretic mobility shift assays showed that PagERF81 directly bound to a GCC sequence in the PagCCR1 promoter. No known vessel or fiber cell differentiation related genes were differentially expressed, so the smaller vessel cells and longer fiber cells observed in the Pagerf81 lines might be caused by abnormal lignin deposition in the secondary cell walls. This study provides insight into the regulation of lignin biosynthesis, and a molecular tool to engineer wood with high lignin content, which would contribute to the lignin‐related chemical industry and carbon sequestration.
The APETALA 2/ethylene‐responsive element binding factor (AP2/ERF) transcription factor PagERF81 plays an important role in lignin biosynthesis and xylem cell differentiation in poplar and the monolignol biosynthesis gene PagCCR1 is a direct target of PagERF81.
There is growing evidence that tripartite motif-containing protein 44 (TRIM44) plays crucial role in tumor development. However, the underlying mechanism of this deubiquitinating enzyme remains ...unclear.
Large clinical samples were used to detect TRIM44 expression and its associations with clinicopathological features and prognosis. Gain- and loss-of-function experiments in cell lines and mouse xenograft models were performed to elucidate the function and underlying mechanisms of TRIM44 induced tumor progression. Co-immunoprecipitation (Co-IP) assays and mass spectrometric analyses were applied to verify the interacting proteins of TRIM44.
We found that TRIM44 was commonly amplified in melanoma tissues compared with paratumoral tissues. TRIM44 expression also positively correlated with more aggressive clinicopathological features, such as Breslow depth (p = 0.025), distant metastasis (p = 0.012), and TNM stage (p = 0.002). Importantly, we found that TRIM44 was an independent indicator of prognosis for melanoma patients. Functionally, overexpression of TRIM44 facilitated cell invasion, migration, apoptosis resistance and proliferation in vitro, and promoted lung metastasis and tumorigenic ability in vivo. Importantly, high level of TRIM44 induced melanoma cell epithelial-mesenchymal transition (EMT), which is one of the most important mechanisms for the promotion of tumor metastasis. Mechanistically, high levels of TRIM44 increased the levels of p-AKT (T308) and p-mTOR (S2448), and a specific AKT inhibitor inhibited TRIM44-induced tumor progression. Co-IP assays and mass spectrometric analyses indicated that TRIM44 overexpression induces cell EMT through activating AKT/mTOR pathway via directly binding and stabilizing TOLL-like receptor 4 (TLR4), and TLR4 interference impeded TRIM44 induced tumor progression. Moreover, we demonstrated that TRIM44 is the target of miR-26b-5p, which is significantly downregulated in melanoma tissues and may be responsible for the overexpression of TRIM44.
TRIM44, regulated by miR-26b-5p, promotes melanoma progression by stabilizing TLR4, which then activates the AKT/mTOR pathway. TRIM44 shows promise as a prognostic predictor and a therapeutic target for melanoma patients.
ATPase associated with a variety of cellular activities (AAA ATPase) family members are closely linked to tumor formation and progression. However, their roles in hepatocellular carcinoma (HCC) ...largely remain unclear.
Bioinformatic analyses of public databases were used to excavate the potential AAA ATPases that may contribute to HCC, and thyroid hormone receptor interactor 13 (TRIP13) was selected to following researches because of its most prominently differential expression. Western blot, qRT-PCR and immunohistochemistry were used to detect the expression of TRIP13 in HCC tissues, and then the relationship between TRIP13 expression and clinicopathological parameters were evaluated. Finally, its functions and potential mechanisms were investigated through a series gain- and loss-of-function strategies both in vitro and in vivo.
TRIP13 was significantly overexpressed in HCC tissues and high level of TRIP13 was closely correlated with a worse clinical outcome. Functionally, elevated TRIP13 facilitated cell proliferation, migration, invasion, and promoted cellular epithelial-mesenchymal transition (EMT) in vitro, while promote tumor growth and lung metastasis in vivo. Mechanistically, TRIP13 interacted with ACTN4 and positively regulated its expression, thus activating the AKT/mTOR pathway to drive tumor progression. Moreover, miR-192-5p served as an upstream regulator of TRIP13 by directly binding to TRIP13 mRNA 3' UTR, which may partially explain the high expression of TRIP13 in HCC.
Our findings identified TRIP13 as a promising candidate oncogene in HCC, and TRIP13 induced cell migration, invasion and metastasis of HCC through the AKT/mTOR signaling via interacting with ACTN4.
Summary
Wood is resulted from the radial growth paced by the division and differentiation of vascular cambium cells in woody plants, and phytohormones play important roles in cambium activity.
Here, ...we identified that PagJAZ5, a key negative regulator of jasmonate (JA) signaling, plays important roles in enhancing cambium cell division and differentiation by mediating cytokinin signaling in poplar 84K (Populus alba × Populus glandulosa).
PagJAZ5 is preferentially expressed in developing phloem and cambium, weakly in developing xylem cells. Overexpression (OE) of PagJAZ5m (insensitive to JA) increased cambium activity and xylem differentiation, while jaz mutants showed opposite results. Transcriptome analyses revealed that cytokinin oxidase/dehydrogenase (CKXs) and type‐A response regulators (RRs) were downregulated in PagJAZ5m OE plants. The bioactive cytokinins were significantly increased in PagJAZ5m overexpressing plants and decreased in jaz5 mutants, compared with that in 84K plants. The PagJAZ5 directly interact with PagMYC2a/b and PagWOX4b. Further, we found that the PagRR5 is regulated by PagMYC2a and PagWOX4b and involved in the regulation of xylem development.
Our results showed that PagJAZ5 can increase cambium activity and promote xylem differentiation through modulating cytokinin level and type‐A RR during wood formation in poplar.
It is well known that when a laser is reflected from a rough surface or transmitted through a diffusive medium, a speckle pattern will be formed at a given observation plane. An important parameter ...of speckle is its size, which for the case of homogeneous illumination, well-known relations for its computation have been derived. This is not the case for structured light beams of non-homogeneous intensity and phase distribution. Here, we propose and demonstrate, using Hermite- and Laguerre-Gaussian light modes, that the mean size of the speckle generated by these structured light beams can be measured assuming a homogeneous illumination. We further provide with mathematical expressions that relate the speckle size to the generalised definition of "spot size". To reinforce our assessment, we compare the mean speckle size generated by structured light modes with that generated by wave fronts of constant phase and amplitude and show that in both cases the mean speckle size is almost identical. Our findings reveal a fundamental property of speckle, which will be of great relevance in many speckle-based applications and will pave the way towards the development of novel applications.
Display omitted
•Dust contained diverse antibiotic resistance genes (ARGs) and microbes.•Airborne particulate matter contained high total relative abundance of ARGs.•Campylobacter spp. positively ...correlated with fluoroquinolone resistance genes.•Staphylococcus spp. positively correlated β-lactams (blaZ, mecA) resistance genes.•Microbes and ARGs in particulate matter posed high risks to patient airways.
Antimicrobial resistance is an increasingly serious threat to public health worldwide. The presence of antibiotic resistance genes (ARGs) in human airways and relevant environments has not received significant attention. In this study, abundances of ARGs and microbes from airborne particulate matter, dust, and human airways in a hospital were profiled using high-throughput qPCR and 16S rRNA gene sequencing. More diverse ARGs and microbes in indoor dust and higher levels of ARGs in particulate matter PM10 and PM2.5 were observed. Macrolides and aminoglycoside resistance genes were the most abundant ARGs in the airway and environmental samples, respectively. Moreover, the co-occurrences of priority pathogens, ARGs, and mobile genetic elements (MGEs) were shown by the Network analysis. Campylobacter spp. and Staphylococcus spp. positively correlated with fluoroquinolone (vatC-02, mexD) and β-lactams (blaZ, mecA) resistance genes, respectively. In this regard, based on SourceTracker analysis, inhalable particles contributed to 4.0% to 5.5% of ARGs in human airway samples, suggesting an important exchange between airborne inhalable particles and human commensals. This study may advance knowledge about ARGs in airborne particulate matter and dust associated environments, reveal their potential link between environments and humans, and provide a new sight and fundamental data for ARG risk assessment.
Despite remarkable advances in treatment, most patients with hepatocellular carcinoma (HCC) respond poorly to anti-programmed cell death 1 (anti-PD1) therapy. A deeper insight into the tolerance ...mechanism of HCC against this therapy is urgently needed.
We performed next-generation sequencing, multiplex immunofluorescence, and dual-color immunohistochemistry and constructed an orthotopic HCC xenograft tumor model to identify the key gene associated with anti-PD1 tolerance. A spontaneously tumorigenic transgenic mouse model, an in vitro coculture system, mass cytometry, and multiplex immunofluorescence were used to explore the biological function of zinc finger protein 64 (ZFP64) on tumor progression and immune escape. Molecular and biochemical strategies like RNA-sequencing, chromatin immunoprecipitation-sequencing and mass spectrometry were used to gain insight into the underlying mechanisms of ZFP64.
We showed that ZFP64 is frequently upregulated in tumor tissues from patients with anti-PD1-resistant HCC. Elevated ZFP64 drives anti-PD1 resistance by shifting macrophage polarization toward an alternative activation phenotype (M2) and fostering an inhibitory tumor microenvironment. Mechanistically, we primarily demonstrated that protein kinase C alpha (PKCα) directly phosphorylates ZFP64 at S226, leading to its nuclear translocation and the transcriptional activation of macrophage colony-stimulating factor (CSF1). HCC-derived CSF1 transforms macrophages to the M2 phenotype to drive immune escape and anti-PD1 tolerance. Notably, Gö6976, a protein kinase inhibitor, and lenvatinib, a multi-kinase inhibitor, reset the tumor microenvironment and restore sensitivity to anti-PD1 by blocking the PKCα/ZFP64/CSF1 axis.
We propose that the PKCα/ZFP64/CSF1 axis is critical for triggering immune evasion and anti-PD1 tolerance. Inhibiting this axis with Gö6976 or lenvatinib overcomes anti-PD1 resistance in HCC.
Despite remarkable treatment progress, most patients with hepatocellular carcinoma respond poorly to anti-PD1 therapy (a type of immunotherapy). A deeper insight into the tolerance mechanisms to this therapy is urgently needed. Herein, we unravel a previously unexplored mechanism linking tumor progression, macrophage polarization, and anti-PD1 resistance, and offer an attractive novel target for anti-PD1 combination therapy, which may benefit patients with hepatocellular carcinoma.
Display omitted
•ZFP64 is frequently upregulated in anti-PD1 resistant HCC.•PKCα/ZFP64/CSF1 axis is critical for triggering immune evasion and anti-PD1 tolerance.•Gö6976 and lenvatinib overcome anti-PD1 resistance by blocking the PKCα/ZFP64/CSF1 axis.•Gö6976 combined with anti-PD1 could be an effective new strategy in HCC therapy.
In this work, carbon nitride (C3N4) powder was oxidized by the Hummers oxidation method, and oxidized carbon nitride (O‐C3N4) was obtained. Epoxy (EP) was modified with O‐C3N4, and then carbon fiber ...fabric/epoxy (CF/EP) composites were prepared by hand‐pasting molding. The O‐C3N4 greatly improves the wettability of EP resin, enhances the interface properties of CF/EP composites, and makes the composites have better mechanical properties. The interlaminar shear strength (ILSS) is increased from 51.75 to 59.68 MPa, the tensile strength is increased from 564.54 to 635.39 MPa, the bending strength is increased from 809.64 to 938.81 MPa, and the impact strength is increased from 73.48 to 84.84 kJ/m2. Meanwhile, the dynamic mechanical properties of composites are also significantly improved. The energy storage modulus is increased from 14.9 to 21.4 GPa, with an increase of 43.6%.
Highlights
Developing carbon fiber composites is conducive to industrial applications.
O‐C3N4 effectively improves the mechanical properties of the composite.
O‐C3N4 has the advantages of simple synthesis, low costs, and light color.
O‐C3N4 is rich in oxygen‐containing functional groups.
Mechanical properties of O‐C3N4/CF/EP composites.
PDF
