To investigate the expression of metadherin (MTDH) for its prognostic value in hepatocellular carcinoma (HCC) and its role in promoting HCC metastasis.
This study employed a tissue microarray ...containing samples from 323 HCC patients to examine the expression of MTDH and its correlation with other clinicopathologic characteristics. The role of MTDH in the regulation of HCC metastasis was investigated both in vitro and in vivo using short hairpin RNA (shRNA)-mediated downregulation of MTDH in HCC cell lines with various metastatic potentials.
The expression of MTDH was markedly higher in HCC tumors than in normal liver tissue. Particularly high MTDH expression was observed in tumors with microvascular invasion, pathologic satellites, poor differentiation, or tumor-node-metastasis stages II to III. Furthermore, the clinical outcome was consistently poorer for the MTDH(high) group than for the MTDH(low) group in the 1-, 3-, and 5-year overall survival (OS) rates and in the 1-, 3-, 5-year cumulative recurrence rates. In a nude mice model, the shRNA-mediated downregulation of MTDH resulted in a reduced migratory capacity in HCC cell lines, as well as a reduction in pulmonary and abdominal metastasis. Furthermore, we found that the expression level of MTDH correlated with four epithelial-mesenchymal transition (EMT) markers. Knockdown of MTDH expression in HCC cell lines resulted in downregulation of N-cadherin and snail, upregulation of E-cadherin, and translocation of β-catenin.
MTDH may promote HCC metastasis through the induction of EMT process and may be a candidate biomarker for prognosis as well as a target for therapy.
Ultrafine HfB2 powders were synthesized by the combination of borothermal reduction of HfO2 and solid solution of 5 mol% TiB2 or 5 mol% TaB2, prototypically, (Hf0.95Ti0.05)B2 and (Hf0.95Ta0.05)B2. ...The influence of substitution on the particle growth, high‐temperature stability, densification, microstructure, and mechanical properties of HfB2 was investigated. Results showed that the particle sizes of HfB2, (Hf0.95Ti0.05)B2 and (Hf0.95Ta0.05)B2 powders prepared by borothermal reduction at 1500°C were 1.73, 0.87, and 0.21 µm, respectively. The substitution of TaB2 led to a greater decrease in particles size than TiB2. After heat treatment at 1800°C, the particle sizes of HfB2, (Hf0.95Ti0.05)B2 and (Hf0.95Ta0.05)B2 powders increased to 2.60, 1.59, and 0.32 µm, respectively, indicative of the good high‐temperature stability of TaB2‐substituted HfB2. The relative densities of HfB2, (Hf0.95Ti0.05)B2 and (Hf0.95Ta0.05)B2 ceramics after spark plasma sintering at 2000°C were 76.1%, 85.2% and 99.8%, respectively. The fully dense (Hf0.95Ta0.05)B2 ceramics with fine microstructure showed comparably high Vickers hardness of 21.1 GPa combined with flexural strength of 521.2 MPa. It was proved that the solid solution of TaB2 could effectively inhibit the grain growth of HfB2 powders, and improve the densification, microstructure, and mechanical properties of HfB2 ceramics.
The modification of insulating materials is regarded as an important way to improve the insulation performance of DC spacers. Many simulations have been carried out to guide the development of ...insulating materials. However, the impacts of temperature on surface charge accumulation and electric field distributions are neglected in many simulations. Since the conductivities are strongly impacted by temperature, the thermal stresses should be considered in the simulations of charge accumulation. To solve these problems, a coupled electro-thermal field simulation model of charge accumulation under DC stress is proposed in this paper. Then, a DC spacer model is introduced as an example, and the parameters in the simulation are shown. Based on the simulation model, the effects of the spacer volume conductivity on the distribution of the surface charge, the saturation time of charge accumulation and the distribution of the electric field along the spacer are investigated. In addition, the influencing mechanism is explained. The results indicate that the volume conductivity of the insulating material should be decreased by two orders of magnitude from the existing AC materials to reduce the surface charge accumulation. With the reduced volume conductivity, 1) the peak value of the charge density on the upper surface decreases 52.9%, and that of lower surface decreases 51.0%; 2) the peak value of the tangential component of the electric field strength along the cone-type spacer in DC-GIL decreases by 12.2%; and 3) the duration of the capacitive-resistive field transition increases by 38.5-fold. The simulation method and advice on the material volume conductivity can be referenced in the DC space design.
Microvascular invasion (MVI) is recognized as a prognostic factor associated with poor outcome in hepatocellular carcinoma (HCC) patients after curative resection. It remains unclear, however, ...whether MVI can provide prognostic information for patients at a specific tumor stage.
Consecutive HCC patients who underwent curative resection in years of 2007 and 2008 (discovery cohort) were enrolled in this retrospective study. Patients were stratified by the Barcelona Clinic Liver Cancer (BCLC) staging system. The prognostic significance of MVI for overall survival (OS) and recurrence-free survival (RFS) was studied in each subgroup. The clinical significance of MVI was validated in another cohort of patients underwent curative surgery in the year of 2006 (validation cohort).
Of the 1540 patients in the discovery cohort, 389 (25.3%) patients had detectable MVI. Occurrence rates of MVI in the BCLC stage 0, A, and B subgroups were 12.4, 26.2, and 34.4%, respectively. In univariate analysis, MVI was associated with poor OS and RFS (P < 0.001 for both) in HCC patients at stage A, with poor OS in patients at stage 0 (P = 0.028), and with poor RFS at stage B (P = 0.039). In multivariate analysis, MVI was an independent risk factor for OS (HR = 1.431, 95% CI, 1.163-1.761, P < 0.001) and RFS (HR = 1.400, 95% CI, 1.150-1.705, P = 0.001) in patients at stage A; and an independent risk factor for RFS (P = 0.043) in patients at stage B. A similar clinical significance of MVI was found in the validation cohort.
MVI has limited prognostic value for HCC patients at BCLC stages 0 and B. For those at stage A, MVI was associated with patient survival and may help to select patients with high risk of disease recurrence.
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently a global pandemic. CoVs are known to generate negative subgenomes (subgenomic ...RNAs sgRNAs) through transcription-regulating sequence (TRS)-dependent template switching, but the global dynamic landscapes of coronaviral subgenomes and regulatory rules remain unclear. Here, using next-generation sequencing (NGS) short-read and Nanopore long-read poly(A) RNA sequencing in two cell types at multiple time points after infection with SARS-CoV-2, we identified hundreds of template switches and constructed the dynamic landscapes of SARS-CoV-2 subgenomes. Interestingly, template switching could occur in a bidirectional manner, with diverse SARS-CoV-2 subgenomes generated from successive template-switching events. The majority of template switches result from RNA-RNA interactions, including seed and compensatory modes, with terminal pairing status as a key determinant. Two TRS-independent template switch modes are also responsible for subgenome biogenesis. Our findings reveal the subgenome landscape of SARS-CoV-2 and its regulatory features, providing a molecular basis for understanding subgenome biogenesis and developing novel anti-viral strategies.
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•Dynamic subgenome landscapes of SARS-CoV-2 in two host cells are constructed•Bidirectional and successive template switching diversify sgRNA biogenesis•Several key determinants governing template switching efficacy are discovered•Canonical TRS-independent RNA-RNA interaction mediates template switches
Wang et al. construct dynamic landscapes of SARS-CoV-2 subgenomic RNAs (sgRNAs) by using integrated poly(A) RNA sequencing at various time points after infection. Computational analyses reveal novel modes of viral sgRNA biogenesis and decode regulatory features, including several key determinants governing the efficacy of template switching in coronaviral RNA transcription.
There is limited understanding of the effects of major oncogenic pathways and their combinatorial actions on lipid composition and transformation during hepatic tumorigenesis. Here, we report a ...negative correlation of Wnt/Myc activity with steatosis in human hepatocellular carcinoma (HCC) and perform
functional studies using three conditional transgenic zebrafish models. Double-transgenic zebrafish larvae conditionally expressing human
and zebrafish
or murine
together with
in hepatocytes led to severe hepatomegaly and significantly attenuated accumulation of lipid droplets and cell senescence triggered by
expression alone. UPLC-MS-based, nontargeted lipidomic profiling and transcriptome analyses revealed that Wnt/Myc activity promotes triacylglycerol to phospholipid transformation and increases unsaturated fatty acyl groups in phospholipids in a Ras-dependent manner. Small-scale screenings suggested that supplementation of certain free fatty acids (FA) or inhibition of FA desaturation significantly represses hepatic hyperplasia of double-transgenic larvae and proliferation of three human HCC cells with and without sorafenib. Together, our studies reveal novel Ras-dependent functions of Wnt signaling in remodeling the lipid metabolism of cancerous hepatocytes in zebrafish and identify the SCD inhibitor MK8245 as a candidate drug for therapeutic intervention.
These findings identify FA desaturation as a significant downstream therapeutic target for antagonizing the combinatorial effects of Wnt and Ras signaling pathways in hepatocellular carcinoma.
http://cancerres.aacrjournals.org/content/canres/78/19/5548/F1.large.jpg
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According to the International Diabetes Federation (IDF),2 the prevalence of diabetes among adults aged 20–79 in 2017 was 8.8% from a total population of 425 million, which will reach 629 million by ...2045. SOD: superoxide dismutase; CAT: catalase; GSH-px: glutathione peroxidase; iNOS: inducible nitric oxide synthase; MDA: malondialdehyde. 34 Therefore, oxidative stress is most harmful to human pancreatic cells, causing diabetes. ...increasing studies35,36 have shown that oxidative stress can induce insulin resistance, which makes more evident that oxidative stress is an important factor in the onset or exacerbation of T2DM. ...anti-oxidative therapy is helpful for the treatment of T2DM.
High-entropy boride ceramics of (Zr0.2Ta0.2Ti0.2Nb0.2Hf0.2)B2 and (Zr0.2W0.2Ti0.2Mo0.2Hf0.2)B2 were prepared by combining powder synthesis via borothermal reduction process at 1600 °C and subsequent ...ceramic densification by spark plasma sintering at 2000 °C in argon. High-entropy diboride powdered products exhibited ultra-fine particle size (<0.5 μm) after borothermal reduction. (Zr0.2Ta0.2Ti0.2Nb0.2Hf0.2)B2 ceramic with the single phase was obtained after sintering. However, the minor phase with the nominal WB composition was detected in (Zr0.2W0.2Ti0.2Mo0.2Hf0.2)B2 ceramic. (Zr0.2W0.2Ti0.2Mo0.2Hf0.2)B2 ceramic exhibited a high relative density associated with the high hardness of 27.7 GPa, which were higher than those measured for (Zr0.2Ta0.2Ti0.2Nb0.2Hf0.2)B2 ceramics (94.0% in relative density and 16.4 GPa in hardness) or the reported values (~92% in relative densities and 17.5–23.7 GPa in hardness) of other high-entropy boride ceramics.
Background & Aims Overexpression of CD151 is associated with poor prognosis for hepatocellular carcinoma (HCC), yet its role in pathogenesis is not known. Methods We analyzed the expression of the ...integrin subunit α6 by quantitative, real-time polymerase chain reaction and immunoblot analyses of 120 HCC tissue samples; its clinical significance was investigated using tissue microarray (TMAs) analysis of samples from 335 patients with HCC. Immunoprecipitation was used to assess the relationship between α6 and CD151. The molecular effects of high expression levels of α6 and CD151 in HCC cells were determined using RNA interference and pharmacologic approaches. Results Overexpression of α6 correlated with poor prognosis of patients with HCC; α6 formed a complex with endogenous CD151 in HCC cells. In cells that expressed high levels of α6 and CD151, laminin-5 promoted cell spreading by inducing the epithelial–mesenchymal transition (EMT); this effect was not observed in cells that expressed high levels of only α6 or CD151. Cells that expressed high levels of α6 and CD151 underwent the EMT in response to laminin-5, through hyperactivation of phosphatidylinositol-3-kinase (PI3K), primarily induced via the PI3K–protein kinase B (Akt)–Snail–phosphatase and tensin homolog feedback pathway. The EMT was reversed by PI3K inhibitors and antibodies against CD151 or α6 in vitro, and was delayed by specific interference with CD151 and α6 in vivo. Conclusions High expression levels of CD151 and α6 promote invasiveness of HCC cells. Either of these proteins, or PI3K signaling, might be targets for therapeutics for subgroups of patients with HCC.
•Hepatocellular carcinoma cells domesticated macrophages toward M2-phenotype polarization.•Human HCC tumor microarrays and in vivo tumor models showed autophagy inhibition of macrophages.•The ...autophagy inhibition of macrophages participated in M2-like macrophage polarization.•The inhibition increased the instability of the NF-κB pathway via ubiquitination degradation of TAB3.
The tumor microenvironment is a highly heterogeneous circumstance composed of multiple components, while tumor-associated macrophages (TAMs) are major innate immune cells with highly plastic and are always educated by tumor cells to structure an advantageous pro-tumor immune microenvironment. Despite emerging evidence focalizing the role of autophagy in other immune cells, the regulatory mechanism of autophagy in macrophage polarization remains poorly understood. Herein, we demonstrated that hepatocellular carcinoma (HCC) cells educated macrophages toward M2-like phenotype polarization under the condition of coculture. Moreover, we observed that inhibition of macrophage autophagy promoted M2-like macrophage polarization, while the tendency was impeded when autophagy was motivated. Mechanistically, macrophage autophagy inhibition inactivates the NF-κB pathway by increasing the instability of TAB3 via ubiquitination degradation, which leads to the M2-like phenotype polarization of macrophages. Both immunohistochemistry staining using human HCC tissues and experiment in vivo verified autophagy inhibition is correlated with M2 macrophage polarization. Altogether, we illustrated that macrophage autophagy was involved in the process of HCC cells domesticating M2 macrophage polarization via the NF-κB pathway. These results provide a new target to interfere with the polarization of macrophages to M2-like phenotype during HCC progression.
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