Autophagy is a conserved method of quality control in which cytoplasmic contents are degraded via lysosomes. Lipophagy, a form of selective autophagy and a novel type of lipid metabolism, has ...recently received much attention. Lipophagy is defined as the autophagic degradation of intracellular lipid droplets (LDs). Although much remains unknown, lipophagy appears to play a significant role in many organisms, cell types, metabolic states, and diseases. It participates in the regulation of intracellular lipid storage, intracellular free lipid levels (e.g., fatty acids), and energy balance. However, it remains unclear how intracellular lipids regulate autophagy. Impaired lipophagy can cause cells to become sensitive to death stimuli and may be responsible for the onset of a variety of diseases, including nonalcoholic fatty liver disease and metabolic syndrome. Like autophagy, the role of lipophagy in cancer is poorly understood, although analysis of specific autophagy receptors has helped to expand the diversity of chemotherapeutic targets. These studies have stimulated increasing interest in the role of lipophagy in the pathogenesis and treatment of cancer and other human diseases.
Emerging evidence indicates that tumor cells release a large amount of exosomes loaded with cargos during tumorigenesis. Exosome secretion is a multi-step process regulated by certain related ...molecules. Long non-coding RNAs (lncRNAs) play an important role in hepatocellular carcinoma (HCC) progression. However, the role of lncRNA HOTAIR in regulating exosome secretion in HCC cells remains unclear.
We analyzed the relationship between HOTAIR expression and exosome secretion-related genes using gene set enrichment analysis (GSEA). Nanoparticle tracking analysis was performed to validate the effect of HOTAIR on exosome secretion. The transport of multivesicular bodies (MVBs) after overexpression of HOTAIR was detected by transmission electron microscopy and confocal microscopy analysis of cluster determinant 63 (CD63) with synaptosome associated protein 23 (SNAP23). The mechanism of HOTAIR's regulation of Ras-related protein Rab-35 (RAB35), vesicle associated membrane protein 3 (VAMP3), and SNAP23 was assessed using confocal co-localization analysis, phosphorylation assays, and rescue experiments.
We found an enrichment of exosome secretion-related genes in the HOTAIR high expression group. HOTAIR promoted the release of exosomes by inducing MVB transport to the plasma membrane. HOTAIR regulated RAB35 expression and localization, which controlled the docking process. Moreover, HOTAIR facilitated the final step of fusion by influencing VAMP3 and SNAP23 colocalization. In addition, we validated that HOTAIR induced the phosphorylation of SNAP23 via mammalian target of rapamycin (mTOR) signaling.
Our study demonstrated a novel function of lncRNA HOTAIR in promoting exosome secretion from HCC cells and provided a new understanding of lncRNAs in tumor cell biology.
In contrast to normal cells, which use the aerobic oxidation of glucose as their main energy production method, cancer cells prefer to use anaerobic glycolysis to maintain their growth and survival, ...even under normoxic conditions. Such tumor cell metabolic reprogramming is regulated by factors such as hypoxia and the tumor microenvironment. In addition, dysregulation of certain signaling pathways also contributes to cancer metabolic reprogramming. Among them, the Hippo signaling pathway is a highly conserved tumor suppressor pathway. The core oncosuppressive kinase cascade of Hippo pathway inhibits the nuclear transcriptional co-activators YAP and TAZ, which are the downstream effectors of Hippo pathway and oncogenic factors in many solid cancers. YAP/TAZ function as key nodes of multiple signaling pathways and play multiple regulatory roles in cancer cells. However, their roles in cancer metabolic reprograming are less clear. In the present review, we examine progress in research into the regulatory mechanisms of YAP/TAZ on glucose metabolism, fatty acid metabolism, mevalonate metabolism, and glutamine metabolism in cancer cells. Determining the roles of YAP/TAZ in tumor energy metabolism, particularly in relation to the tumor microenvironment, will provide new strategies and targets for the selective therapy of metabolism-related cancers.
The success of targeted drug therapy for cancer patients has attracted extensive attention from academia and society. However, the rapid development of acquired drug resistance is becoming a major ...challenge. Autophagy, as an essential homeostatic and catabolic process, is crucial for the degradation or recycling of proteins and cellular components. Autophagy has a crucial role in several cellular functions and its dysregulation is associated with tumorigenesis, tumor–stroma interactions, and resistance to cancer therapy. A growing body of evidence shows that in multiple types of cancer, autophagy is also a key regulator in the tumor microenvironment and the cellular drug response. However, our understanding of the process of autophagy remains incompletely. In this review, we identify the role of autophagy and describe recent advances in the identification of the mechanism by which autophagy is implicated in drug resistance, with a focus on the mode of action, and validation as potential therapeutics.
Various methods for differential expression analysis have been widely used to identify features which best distinguish between different categories of samples. Multiple hypothesis testing may leave ...out explanatory features, each of which may be composed of individually insignificant variables. Multivariate hypothesis testing holds a non-mainstream position, considering the large computation overhead of large-scale matrix operation. Random forest provides a classification strategy for calculation of variable importance. However, it may be unsuitable for different distributions of samples.
Based on the thought of using an ensemble classifier, we develop a feature selection tool for differential expression analysis on expression profiles (i.e., ECFS-DEA for short). Considering the differences in sample distribution, a graphical user interface is designed to allow the selection of different base classifiers. Inspired by random forest, a common measure which is applicable to any base classifier is proposed for calculation of variable importance. After an interactive selection of a feature on sorted individual variables, a projection heatmap is presented using k-means clustering. ROC curve is also provided, both of which can intuitively demonstrate the effectiveness of the selected feature.
Feature selection through ensemble classifiers helps to select important variables and thus is applicable for different sample distributions. Experiments on simulation and realistic data demonstrate the effectiveness of ECFS-DEA for differential expression analysis on expression profiles. The software is available at http://bio-nefu.com/resource/ecfs-dea.
Long noncoding RNAs (lncRNAs) has been acknowledged in tumorigenesis gradually because of the great importance in different cancers. LncRNA nuclear enriched abundant transcript 1 (NEAT1) is a novel ...lncRNA and has been reported to promote multiple cancer progression. However, the biological roles of NEAT1 in hepatocellular carcinoma (HCC) is not cleared nowadays. In the present research, the level of NEAT1 was found to be upregulated in HCC by The Cancer Genome Atlas. In addition, NEAT1 expression is negatively correlated with the survival rate in HCC. Further investigation revealed that NEAT1 upregulation inhibited sorafenib efficacy and promoted autophagy. We found that NEAT1 could be a sponge for microRNA‐204 (miR‐204) and inhibits its level to upregulate ATG3 expression. In addition to the above, we demonstrated that miR‐204 mimics also attenuated tumor autophagy. And rescue assays demonstrated that NEAT1 promotes HCC autophagy through modulating miR‐204/ATG3 pathway. Collectively, this study first demonstrated that a novel NEAT1/miR‐204/ATG3 signaling regulates HCC progression.
Nuclear enriched abundant transcript 1 (NEAT1) could be a sponge for microRNA‐204 (miR‐204) and inhibits its level to upregulate ATG3 expression. We demonstrated that miR‐204 mimics also attenuated tumor autophagy. And rescue assays demonstrated that NEAT1 promotes hepatocellular carcinoma (HCC) autophagy through modulating miR‐204/ATG3 pathway.
Hypoxia-inducible factor 1α (HIF-1α) is essential in hepatocellular carcinoma (HCC) glycolysis and progression. Yes-associated protein (YAP) is a powerful regulator and is overexpressed in many ...cancers, including HCC. The regulatory mechanism of YAP and HIF-1α in HCC glycolysis is unknown.
We detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. The relationship between YAP mRNA expression and that of HIF-1α was analyzed using The Cancer Genome Atlas HCC tissue data. We cultured HepG2 and Huh7 HCC cells under normoxic (20% O
) and hypoxic (1% O
) conditions, and measured the lactate and glucose levels, migration and invasive capability, and the molecular mechanism of HCC cell glycolysis and progression.
In this study, we detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. We observed that hypoxia-induced YAP activation is crucial for accelerating HCC cell glycolysis. Hypoxia inhibited the Hippo signaling pathway and promoted YAP nuclear localization, and decreased phosphorylated YAP expression in HCC cells. YAP knockdown inhibited HCC cell glycolysis under hypoxic. Mechanistically, hypoxic stress in the HCC cells promoted YAP binding to HIF-1α in the nucleus and sustained HIF-1α protein stability to bind to PKM2 gene and directly activates PKM2 transcription to accelerate glycolysis.
Our findings describe a new regulatory mechanism of hypoxia-mediated HCC metabolism, and YAP might be a promising therapeutic target in HCC.
The physical and chemical pressures in the tumor microenvironment (TME) play an important role in tumor development by regulating stromal elements, including immune cells. Hypoxia can induce a ...cascade of events in tumor initiation and development via immune regulation. As a dangerous factor, hypoxia activates multiple signaling pathways to reshape the immune microenvironment, leading to immunosuppression. Consequently, targeting hypoxia in the TME is a potential strategy to prevent immune escape and inhibit malignant tumor progression. In this review, we summarized the role of hypoxia-induced factors in the tumor immune escape process and provide a novel pathway to restrain tumor progression and development.
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•Hypoxia is a common character in many solid tumors and involved in tumor progression and development.•Immune cell in tumor microenvironment is a large class of cell groups and is necessary for tumor treatment.•Hypoxia can regulate various immune cellular process leading to immune cell losing its function.•Targeting hypoxia to improve immune treatment is a novel and potential line.
To clarify the effect of electric load characteristics on the arc-erosion behavior of Ag base electrical contact material, the Ag-4 wt.%TiB
2
-4 wt.%Ni contact material was fabricated by spark plasma ...sintering, and the arc-erosion tests were performed at inductive load 18, 24 and 30 V and resistive load 30 V. The microstructure of the material was characterized by scanning electron microscopy and transmission electron microscopy, and the eroded morphology was examined by laser scanning confocal microscopy and scanning electron microscopy equipped with an energy dispersive spectroscopy (EDS). The arc-erosion mechanism was discussed based on the analysis of arc-duration, arc-energy, welding force and arc voltage/current waveforms. The results showed that there is less arc erosion under the resistive load as compared to the inductive load at the same voltage. The EDS analysis demonstrated that Ti and Ni are oxidized during arc erosion, which results in the decrease in the contact stability and the increase in make-arc-duration/energy and its standard deviation. Moreover, a larger mass loss occurs under the inductive load as compared to the resistive load, which can be attributed to the current/voltage shock triggered by the inductor during make operations.
The poor interface bonding between graphene and copper matrix significantly impair the strengthening effect of graphene, but it can be improved by graphene modification. In this work, the Ni-rGO ...compound powders were synthesized via hydrothermal method, and the Cu matrix bulk composites reinforced by Ni-rGO and rGO were prepared by the molecular-level mixing method along with spark plasma sintering, respectively. The sintered bulk materials were examined by transmission electron microscope, scanning electron microscope, Raman spectroscope and X-ray diffractometer, and the mechanical and electrical properties were tested as well. The results indicated that the incorporation of Ni-rGO exhibits a more obvious strengthening effect. As compared to the 0.1wt.%rGO/Cu composite material, the yield strength, tensile strength and elongation of the 0.1wt.%Ni-rGO/Cu composite material are increased by 10.9, 13.5 and 23.9%, respectively. This can be ascribed to the modified structure of graphene along with the improved interface bonding by the incorporation of Ni nanoparticles in rGO.
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