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Histones methyltransferase NSD3 targeting H3K36 is frequently disordered and mutant in various cancers, while the function of NSD3 during cancer initiation and progression remains unclear. In this study, it is proved that downregulated level of NSD3 is linked to clinical features and poor survival in lung adenocarcinoma. In vivo, NSD3 inhibited the proliferation, immigration, and invasion ability of lung adenocarcinoma. Meanwhile, NSD3 suppressed glycolysis by inhibiting HK2 translation, transcription, glucose uptake, and lactate production in lung adenocarcinoma. Mechanistically, as an intermediary, NSD3 binds to PPP1CB and p-STAT3 in protein levels, thus forming a trimer to dephosphorylate the level of p-STAT3 by PPP1CB, leading to the suppression of HK2 transcription. Interestingly, the phosphorylation function of PPP1CB is related to the concentration of carbon dioxide and pH value in the culture environment. Together, this study revealed the critical non-epigenetic role of NSD3 in the regulation of STAT3-dependent glycolysis, providing a piece of compelling evidence for targeting the NSD3/PPP1CB/p-STAT3 in lung adenocarcinoma.
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Background: Breast cancer is the leading cause of cancer-related death in women. Necroptosis, a form of programmed necrotic cell death, occurs in many solid tumors, including breast cancer, and influences anti-tumor immunity. The role of necroptosis in managing breast cancer recurrence remains unclear. Methods: Gene expression profiles and clinical data of breast cancer patients were obtained from the GEO (GSE20685, GSE21653, GSE25055) and TCGA databases. Data analysis and visualization were performed using R. Unsupervised Consensus Clustering and LASSO-COX regression stratified breast cancer patients. GO, KEGG, GSVA, ESTIMATE, and ROC analyses were used to investigate necroptotic signatures. In vitro and in vivo experiments validated necroptosis's role in breast cancer immunity. Results: The potential function of necroptotic signature in immunity was first indicated with GO analysis in BRCA cohort. Next, two prognostic models based on the necroptotic profiles both suggested a link between low-risk group with a particular necroptotic immune signature. And a variety of immune cells and immune pathways were shown to be positively associated with a patient's risk score. As an altered immune checkpoint pattern was observed after regulating necroptotic genes, where TIM-3 and LAGLS9 elevated significantly in low-risk group, further validation in vitro and in vivo demonstrated that manipulating a subset of necroptotic gene set could sensitize tumor response to the co-blockade immunotherapy of anti-TIM-3 and anti-PD-1. Conclusion: We demonstrated two strategies to stratify breast cancer patients based on their necroptotic profiles and showed that necroptotic signature could assign patients with different tumor immune microenvironment patterns and different recurrence-related prognosis. A subset of necroptotic gene set, composed of TLR3, RIPK3, NLRP3, CASP1, ALDH2 and EZH2, was identified as a biomarker set for predicting immunotherapy-response and recurrence-related prognosis. Targeting necroptosis could helpfacilitate the development of novel breast cancer treatments and tailor personalized medical treatment.
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Ubiquitination was considered to be a crucial factor in intrahepatic cholangiocarcinoma (iCCA) development. Herein, we identified Ubiquitin-specific peptidase 8 (USP8) as a key regulator for promoting the tumorigenesis of iCCA cell via stabilizing OGT. USP8 was overexpressed in human tumor tissues and correlated with worse survival. Moreover, the mass spectrometry and co-immunoprecipitation analysis indicated that USP8 interacted with OGT. USP8 worked as a bona fide deubiquitylase of OGT. It stabilized OGT in a deubiquitylation activity-dependent manner. Meanwhile, DUB-IN3, the USP8 inhibitor, could also restrain the malignancy of intrahepatic cholangiocarcinoma. In addition, USP8 depletion promoted the response of iCCA to pemigatinib. In conclusion, our findings pointed to a previously undocumented catalytic role for USP8 as a deubiquitinating enzyme of OGT. The USP8-OGT axis could be a potential target for iCCA therapy.
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We model and demonstrate a self-matching photonic lantern (SMPL) device, which is designed to address the constraint of limited transverse modes generated by fiber lasers. The SMPL incorporates a FMF into the array at the input end of a traditional photonic lantern. The few-mode fiber at the output end is specifically configured to align with the few-mode fiber at the input, therefore named as SMPL. This paper details the design and fabrication of the SMPL device, validated by both simulation and experiment. The 980nm fundamental mode, injected via 980nm single-mode fibers, selectively excites corresponding higher-order modes at the few-mode port of the SMPL. Additionally, 1550nm fundamental and higher-order modes injected at the input end into the SMPL device demonstrates mode preservation and low-loss transmission characteristics. The SMPL is well-suited for developing a ring laser system, enabling selective excitation of 980nm pump light modes and facilitating closed-loop oscillation and transmission of 1550nm laser.
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As a major cause of low back pain, intervertebral disc degeneration is an increasingly prevalent chronic disease worldwide that leads to huge annual financial losses. The intervertebral disc consists of the inner nucleus pulposus, outer annulus fibrosus, and sandwiched cartilage endplates. All these factors collectively participate in maintaining the structure and physiological functions of the disc. During the unavoidable degeneration stage, the degenerated discs are surrounded by a harsh microenvironment characterized by acidic, oxidative, inflammatory, and chaotic cytokine expression. Loss of stem cell markers, imbalance of the extracellular matrix, increase in inflammation, sensory hyperinnervation, and vascularization have been considered as the reasons for the progression of intervertebral disc degeneration. The current treatment approaches include conservative therapy and surgery, both of which have drawbacks. Novel stimuli-responsive delivery systems are more promising future therapeutic options than traditional treatments. By combining bioactive agents with specially designed hydrogels, scaffolds, microspheres, and nanoparticles, novel stimuli-responsive delivery systems can realize the targeted and sustained release of drugs, which can both reduce systematic adverse effects and maximize therapeutic efficacy. Trigger factors are categorized into internal (pH, reactive oxygen species, enzymes, etc.) and external stimuli (photo, ultrasound, magnetic, etc.) based on their intrinsic properties. This review systematically summarizes novel stimuli-responsive delivery systems for intervertebral disc degeneration, shedding new light on intervertebral disc therapy.
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Degeneración del Disco Intervertebral , Humanos , Degeneración del Disco Intervertebral/terapia , Sistemas de Liberación de Medicamentos/métodos , Animales , Nanopartículas/química , Hidrogeles/química , Disco Intervertebral/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
PURPOSE: Directly imaging the function of cerebral perforating arteries could provide valuable insight into the pathology of cerebral small vessel diseases (cSVD). Arterial pulsatility has been identified as a useful biomarker for assessing vascular dysfunction. In this study, we investigate the feasibility and reliability of using dual velocity encoding (VENC) phase-contrast MRI (PC-MRI) to measure the pulsatility of cerebral perforating arteries at 7 T. METHODS: Twenty participants, including 12 young volunteers and 8 elder adults, underwent high-resolution 2D PC-MRI scans with VENCs of 20 cm/s and 40 cm/s at 7T. The sensitivity of perforator detection and the reliability of pulsatility measurement of cerebral perforating arteries using dual-VENC PC-MRI were evaluated by comparison with the single-VENC data. The effects of temporal resolution in the PC-MRI acquisition and aging on the pulsatility measurements were investigated. RESULTS: Compared to the single VENCs, dual-VENC PC-MRI provided improved sensitivity of perforator detection and more reliable pulsatility measurements. Temporal resolution impacted the pulsatility measurements, as decreasing temporal resolution led to an underestimation of pulsatility. Elderly adults had elevated pulsatility in cerebral perforating arteries compared to young adults, but there was no difference in the number of detected perforators between the two age groups. CONCLUSION: Dual-VENC PC-MRI is a reliable imaging method for the assessment of pulsatility of cerebral perforating arteries, which could be useful as a potential imaging biomarker of aging and cSVD.
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Arterias Cerebrales , Imagen por Resonancia Magnética , Flujo Pulsátil , Humanos , Femenino , Masculino , Adulto , Anciano , Reproducibilidad de los Resultados , Arterias Cerebrales/diagnóstico por imagen , Arterias Cerebrales/fisiología , Flujo Pulsátil/fisiología , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Adulto Joven , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Circulación Cerebrovascular/fisiología , Velocidad del Flujo Sanguíneo/fisiología , Angiografía por Resonancia Magnética/métodos , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
Hepatocellular carcinoma (HCC) is the most common type of primary hepatic liver cancer. Dysregulated Wnt/ß-catenin activation is closely related to the progression of cancer. Nevertheless, the mechanism that sustains the abnormal expression of ß-catenin in HCC has yet to be identified. In this study, we find that UCHL3 is overexpressed in HCC tissues and correlated with ß-catenin protein level. High expression of UCHL3 is associated with poor prognosis. UCHL3 knockdown markedly reduces the protein level of ß-catenin in HCC cells. TOP-luciferase activity and ß-catenin target genes expression are also decreased upon UCHL3 depletion. We find that the ARM domain of ß-catenin is required for the interaction with UCHL3. UCHL3 increases ß-catenin protein stability via removing K48-specific poly-ubiquitin chains from ß-catenin protein. Furthermore, the depletion of UCHL3 induces ferroptosis and hinders the growth, invasion, and stem cell properties of HCC cells. These impacts could be restored by the overexpression of ß-catenin. In addition, the UCHL3 inhibitor TCID inhibits the aggressive phenotype of HCC through the degradation of ß-catenin. In general, our results indicates that UCHL3 increases the stability of ß-catenin, which in turn facilitates tumorigenesis of HCC, suggesting that targeting UCHL3 may be a promising approach for the treatment of HCC.
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Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , beta Catenina/genética , beta Catenina/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proliferación Celular/genética , Ubiquitina Tiolesterasa/genéticaRESUMEN
Oxaliplatin (OXA) resistance is a major clinic challenge in hepatocellular carcinoma (HCC). Ferroptosis is a kind of iron-dependent cell death. Triggering ferroptosis is considered to restore sensitivity to chemotherapy. In the present study, we found that USP20 was overexpressed in OXA-resistant HCC cells. High expression of USP20 in HCC was associated with poor prognosis. USP20 contributes OXA resistance and suppress ferroptosis in HCC. Pharmacological inhibition or knockdown of USP20 triggered ferroptosis and increased the sensitivity of HCC cells to OXA both in vitro and in vivo. Coimmunoprecipitation results revealed that the UCH domain of USP20 interacted with the N terminal of SLC7A11. USP20 stabilized SLC7A11 via removing K48-linked polyubiquitination of SLC7A11 protein at K30 and K37. Most importantly, DNA damage-induced ATR activation was required for Ser132 and Ser368 phosphorylation of USP20. USP20 phosphorylation at Ser132 and Ser368 enhanced its stability and thus conferred OXA and ferroptosis resistance of HCC cells. Our study reveals a previously undiscovered association between OXA and ferroptosis and provides new insight into mechanisms regarding how DNA damage therapies always lead to therapeutic resistance. Therefore, targeting USP20 may mitigate the development of drug resistance and promote ferroptosis of HCC in patients receiving chemotherapy.
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The COVID-19 pandemic continues to affect the world. Wuhan, the epicenter of the outbreak, underwent a 76-day lockdown. Research has indicated that the lockdown negatively impacted the quality of life of older individuals, but little is known about their specific experiences during the confinement period. Qualitative interviews were conducted with 20 elderly residents of Wuhan, aged 65 to 85, who experienced mandatory isolation throughout the pandemic. The interviews centered around three stages of experiences: the Early Lockdown stage (the first week of lockdown after the government implemented the lockdown policy in January 2020), Infection During Lockdown stage (from February to April 2020 when participants were affected by the lockdown), and the Post-Lockdown stage (after April 2020 when the government lifted the lockdown policy). We found that older adults experienced different core themes during each lockdown stage. In the Early Lockdown stage, they felt nervousness and fear while searching for information. During the Lockdown and Infection Stage, they relied on reciprocal support and adjusted to new lifestyles. In the Post-Lockdown stage, they expressed cautions, trust, and gratitude. The finding highlights the evolving emotions and coping strategies of older adults throughout the lockdown phases. This study has yielded valuable insights into the adaptations of behavior and the importance of social interactions, specifically emphasizing the significance of healthcare among the elderly population.
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Hepatocellular carcinoma (HCC) is a lethal and aggressive human malignancy. The present study examins the anti-tumor effects of deubiquitylating enzymes (DUB) inhibitors in HCC. It is found that the inhibitor of ubiquitin specific peptidase 8 (USP8) and DUB-IN-3 shows the most effective anti-cancer responses. Targeting USP8 inhibits the proliferation of HCC and induces cell ferroptosis. In vivo xenograft and metastasis experiments indicate that inhibition of USP8 suppresses tumor growth and lung metastasis. DUB-IN-3 treatment or USP8 depletion decrease intracellular cystine levels and glutathione biosynthesis while increasing the accumulation of reactive oxygen species (ROS). Mechanistical studies reveal that USP8 stabilizes O-GlcNAc transferase (OGT) via inhibiting K48-specific poly-ubiquitination process on OGT protein at K117 site, and STE20-like kinase (SLK)-mediated S716 phosphorylation of USP8 is required for the interaction with OGT. Most importantly, OGT O-GlcNAcylates solute carrier family 7, member 11 (SLC7A11) at Ser26 in HCC cells, which is essential for SLC7A11 to import the cystine from the extracellular environment. Collectively, this study demonstrates that pharmacological inhibition or knockout of USP8 can inhibit the progression of HCC and induce ferroptosis via decreasing the stability of OGT, which imposes a great challenge that targeting of USP8 is a potential approach for HCC treatment.
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Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , Humanos , Cistina , Endopeptidasas , Ubiquitina Tiolesterasa , Complejos de Clasificación Endosomal Requeridos para el Transporte , Sistema de Transporte de Aminoácidos y+RESUMEN
Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal human malignancies, and with quite limited treatment alternatives. The proteasome is responsible for most of the protein degradation in eukaryotic cells and required for the maintenance of intracellular homeostasis. However, its potential role in HCC is largely unknown. In the current study, we identified eukaryotic translation initiation factor 3 subunit H (EIF3H), belonging to the JAB1/MPN/MOV34 (JAMM) superfamily, as a bona fide deubiquitylase of O-GlcNAc transferase (OGT) in HCC. We explored that EIF3H was positively associated with OGT in HCC and was related to the unfavorable prognosis. EIF3H could interact with, deubiquitylate, and stabilize OGT in a deubiquitylase-dependent manner. Specifically, EIF3H was associated with the GT domain of ERα via its JAB/MP domain, thus inhibiting the K48-linked ubiquitin chain on OGT. Besides, we demonstrated that the knockdown of EIF3H significantly reduced OGT protein expression, cell proliferation and invasion, and caused G1/S arrest of HCC. We also found that the deletion of EIF3H prompted ferroptosis in HCC cells. Finally, the effects of EIF3H depletion could be reversed by further OGT overexpression, implying that the OGT status is indispensable for EIF3H function in HCC carcinogenesis. In summary, our study described the oncogenic function of EIF3H and revealed an interesting post-translational mechanism between EIF3H, OGT, and ferroptosis in HCC. Targeting the EIF3H may be a promising approach in HCC. Video Abstract.
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Carcinoma Hepatocelular , Factor 3 de Iniciación Eucariótica , Ferroptosis , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Enzimas Desubicuitinizantes , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Factor 3 de Iniciación Eucariótica/genética , Factor 3 de Iniciación Eucariótica/metabolismoRESUMEN
Tryptophan metabolism is associated with tumorigenesis and tumor immune response in various cancers. Liver is the main place where tryptophan catabolism is performed. However, the role of tryptophan metabolism in hepatocellular carcinoma (HCC) has not been well clarified. In the present study, we described the mutations of 42 tryptophan metabolism-related genes (TRPGs) in HCC cohorts. Then, HCC patients were well distributed into two subtypes based on the expression profiles of the 42 TRPGs. The clinicopathological characteristics and tumor microenvironmental landscape of the two subtypes were profiled. We also established a TRPGs scoring system and identified four hallmark TRPGs, including ACSL3, ADH1B, ALDH2, and HADHA. Univariate and multivariate Cox regression analysis revealed that the TRPG signature was an independent prognostic indicator for HCC patients. Besides, the predictive accuracy of the TRPG signature was assessed by the receiver operating characteristic curve (ROC) analysis. These results showed that the TRPG risk model had an excellent capability in predicting survival in both TCGA and GEO HCC cohorts. Moreover, we discovered that the TRPG signature was significantly related to the different immune infiltration and therapeutic drug sensitivity. The functional experiments and immunohistochemistry staining analysis also validated the results above. Our comprehensive analysis enhanced our understanding of TRPGs in HCC. A novel predictive model based on TRPGs was built, which may be considered as a beneficial tool for predicting the clinical outcomes of HCC patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Triptófano , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Pronóstico , Inmunoterapia , Aldehído Deshidrogenasa MitocondrialRESUMEN
Hepatocellular carcinoma (HCC) is the most common type of primary hepatic carcinoma, which is a growing public health problem worldwide. One of the main genetic alterations in HCC is the deregulated Wnt/ß-catenin signaling, activation of ß-catenin is associated with the progression of HCC. In the present study, we aimed to identify novel modulators in controlling ß-catenin ubiquitination and stability. USP8 was overexpressed in HCC tissues and correlated with ß-catenin protein level. High expression of USP8 indicated poor prognosis of HCC patients. USP8 depletion significantly decreased ß-catenin protein level, ß-catenin target genes expression and TOP-luciferase activity in HCC cells. Further mechanistic study revealed that the USP domain of USP8 interacted with the ARM domain of ß-catenin. USP8 stabilized ß-catenin protein via inhibiting K48-specific poly-ubiquitination process on ß-catenin protein. In addition, USP8 depletion inhibited the proliferation, invasion and stemness of HCC cells and conferred ferroptosis resistance, which effects could be further rescued by ß-catenin overexpression. In addition, the USP8 inhibitor DUB-IN-3 inhibited the aggressive phenotype and promoted ferroptosis of HCC cells through degradation of ß-catenin. Thus, our study demonstrated that USP8 activated the Wnt/beta-catenin signaling through a post-translational mechanism of ß-catenin. High expression of USP8 promoted the progression and inhibited ferroptosis of HCC. Targeting the USP8 may serve as a promising strategy for patients with HCC.
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Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , beta Catenina , Neoplasias Hepáticas/genética , Carcinogénesis/genética , Transformación Celular Neoplásica , Cateninas , Endopeptidasas , Ubiquitina Tiolesterasa/genética , Complejos de Clasificación Endosomal Requeridos para el TransporteRESUMEN
BACKGROUND: Prostate cancer (PC) is the most common neoplasm and is the second leading cause of cancer-related deaths in men worldwide. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal YAP expression in PC remains to be characterized. METHODS: Western blot was used to measure the protein expression of ATXN3 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; transwell invasion assay was used to measure the invasion ability of PC. The xeno-graft tumor model was used for in vivo study. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between YAP and ATXN3. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. RESULTS: In the present study, we identified ATXN3, a DUB enzyme in the ubiquitin-specific proteases family, as a bona fide deubiquitylase of YAP in PC. ATXN3 was shown to interact with, deubiquitylate, and stabilize YAP in a deubiquitylation activity-dependent manner. Depletion of ATXN3 decreased the YAP protein level and the expression of YAP/TEAD target genes in PC, including CTGF, ANKRD1 and CYR61. Further mechanistic study revealed that the Josephin domain of ATXN3 interacted with the WW domain of YAP. ATXN3 stabilized YAP protein via inhibiting K48-specific poly-ubiquitination process on YAP protein. In addition, ATXN3 depletion significantly decreased PC cell proliferation, invasion and stem-like properties. The effects induced by ATXN3 depletion could be rescued by further YAP overexpression. CONCLUSIONS: In general, our findings establish a previously undocumented catalytic role for ATXN3 as a deubiquitinating enzyme of YAP and provides a possible target for the therapy of PC. Video Abstract.
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Neoplasias de la Próstata , Transducción de Señal , Masculino , Animales , Humanos , Factores de Transcripción/metabolismo , Línea Celular Tumoral , Neoplasias de la Próstata/patología , Vía de Señalización Hippo , Proliferación Celular , Mamíferos/metabolismo , Ataxina-3/metabolismo , Proteínas Represoras/metabolismoRESUMEN
Raptor, a key component of mTORC1, is required for recruiting substrates to mTORC1 and contributing to its subcellular localization. Raptor has a highly conserved N-terminus domain and seven WD40 repeats, which interact with mTOR and other mTORC1-related proteins. mTORC1 participates in various cellular events and mediates differentiation and metabolism. Directly or indirectly, many factors mediate the differentiation and function of lymphocytes that is essential for immunity. In this review, we summarize the role of Raptor in lymphocytes differentiation and function, whereby Raptor mediates the secretion of cytokines to induce early lymphocyte metabolism, development, proliferation and migration. Additionally, Raptor regulates the function of lymphocytes by regulating their steady-state maintenance and activation.
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Citocinas , Transducción de Señal , Proteína Reguladora Asociada a mTOR/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Citocinas/metabolismoRESUMEN
Yes-associated protein (YAP) is one of major key effectors of the Hippo pathway and the mechanism supporting abnormal YAP expression in Anaplastic thyroid carcinoma (ATC) remains to be characterized. Here, we identified ubiquitin carboxyl terminal hydrolase L3 (UCHL3) as a bona fide deubiquitylase of YAP in ATC. UCHL3 stabilized YAP in a deubiquitylation activity-dependent manner. UCHL3 depletion significantly decreased ATC progression, stem-like and metastasis, and increased cell sensitivity to chemotherapy. Depletion of UCHL3 decreased the YAP protein level and the expression of YAP/TEAD target genes in ATC. UCHL3 promoter analysis revealed that TEAD4, through which YAP bind to DNA, activated UCHL3 transcription by binding to the promoter of UCHL3. In general, our results demonstrated that UCHL3 plays a pivotal role in stabilizing YAP, which in turn facilitates tumorigenesis in ATC, suggesting that UCHL3 may prove to be a potential target for the treatment of ATC.
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Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Vía de Señalización Hippo , Carcinoma Anaplásico de Tiroides/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo , Neoplasias de la Tiroides/genética , Factores de Transcripción de Dominio TEARESUMEN
Radix Pseudostellariae, a traditional Chinese medicine, functions in modulating human immunity and anti-tumor, but its pharmacological mechanism remained unclear. In this study, 8 active components and 91 targets of Radix Pseudostellariae were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, and 225 genes related to gastric cancer (GC) were accessed from MalaCards. On the basis of these targets and GC-related genes, a protein-protein interaction (PPI) network was established. Random walk with restart (RWR) analysis was performed on the PPI network with the intersection of targets and GC-related genes as the seeds. The top 50 target genes with high affinity scores were obtained. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that the enrichment of the top 50 genes was mostly presented in the cancer-related biological functions and signaling pathways, such as cellular response to oxidative stress, regulation of apoptotic signaling pathway, and P53 signaling pathway. A drug-component-target network was established, with the top 50 genes being used as key targets. Acacetin and luteolin were revealed to directly act on the core target TP53 in the network. Thus, SwissDock was used to simulate the molecular docking between TP53 protein and acacetin and luteolin. The results of docking simulation presented small estimated ΔG of two small molecules, which were suggested to be potential targets of TP53 protein. Subsequent cellular and molecular experiments confirmed this bioinformatics result. In conclusion, this study predicted the key anti-GC active components and corresponding targets of Radix Pseudostellariae through bioinformatics analysis. The findings underlie the anti-GC mechanism of Radix Pseudostellariae.
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Medicamentos Herbarios Chinos , Neoplasias Gástricas , Humanos , Simulación del Acoplamiento Molecular , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Farmacología en Red , Luteolina , Proteína p53 Supresora de Tumor , Medicamentos Herbarios Chinos/farmacología , Medicina Tradicional ChinaRESUMEN
Heterophyllin B (HB) is a cyclic lipopeptide that has been shown to have anticancer effects. This study intended to further explore the effects and modulatory mechanism of HB in gastric cancer (GC) cells. The binding relationship between HB and CXCR4 was investigated by network pharmacological analysis, molecular docking, and cellular thermal shift assay (CETSA)-WB assay. Cellular assays revealed that HB could restrain GC cell viability, proliferation, invasion and migration by binding to CXCR4. Further studies presented that HB could suppress PI3K/AKT signaling pathway via binding to CXCR4, thus repressing PD-L1 expression. In vivo experiments in nude mice demonstrated that HB constrained PI3K/AKT signaling pathway to suppress GC cell metastasis and PD-L1 expression. In summary, the key target of HB in GC treatment was CXCR4. Cell experiments were employed for the investigation of the mechanism by which HB repressed GC cells. The results confirmed that HB could constrain the malignant progression of GC by the binding of HB into CXCR4 and suppressed PD-L1 expression via hampering PI3K/AKT signaling pathway.
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Neoplasias Gástricas , Animales , Ratones , Neoplasias Gástricas/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Antígeno B7-H1/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones Desnudos , Simulación del Acoplamiento Molecular , Proliferación Celular/genética , Transducción de Señal , Fenotipo , Movimiento Celular/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión GénicaRESUMEN
Breast cancer is a major cause of cancer-related morbidity and mortality in women. Estrogen receptor-positive breast cancer accounts for roughly 70%-80% of breast tumors, and estrogen receptor alpha (ERα) has been considered as a key driver in promoting breast cancer progression. In the present study, we identified USP37 as a novel modulator in modulating ERα ubiquitination and stability. The expression of USP37 was upregulated in ERα-positive breast cancer and correlated with ERα protein level. High expression of USP37 was associated with unfavorable prognosis. USP37 depletion resulted in significantly decreased ERα protein level, ERα target genes expression as well as the estrogen response element activity in breast cancer cells. Further mechanistic study revealed the interaction between USP37 and ERα: USP37 regulated ERα signaling through modulating protein stability instead of gene expression, in which it stabilized ERα protein via inhibiting the K48-specific polyubiquitination process. Additionally, USP37 depletion led to growth inhibition and cell cycle arrest of ERα-positive breast cancer cells, which could be further rescued by ERα overexpression. Overall, our study proposed a novel post-translational mechanism of ERα in promoting breast cancer progression. Targeting USP37 may be proved to be a promising strategy for patients with ERα-positive breast cancer.
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Neoplasias de la Mama , Endopeptidasas , Receptor alfa de Estrógeno , Femenino , Humanos , Mama/patología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Estrógenos , Regulación Neoplásica de la Expresión Génica , Células MCF-7 , Endopeptidasas/metabolismoRESUMEN
Background: Hepatocellular carcinoma (HCC) is an aggressive and heterogeneous disease characterized by high morbidity and mortality. The liver is the vital organ that participates in tyrosine catabolism, and abnormal tyrosine metabolism could cause various diseases, including HCC. Besides, the tumor immune microenvironment is involved in carcinogenesis and can influence the patients' clinical outcomes. However, the potential role of tyrosine metabolism pattern and immune molecular signature is poorly understood in HCC. Methods: Gene expression, somatic mutations, copy number variation data, and clinicopathological information of HCC were downloaded from The Cancer Genome Atlas (TCGA) database. GSE14520 from the Gene Expression Omnibus (GEO) databases was used as a validation dataset. We performed unsupervised consensus clustering of tyrosine metabolism-related genes (TRGs) and classified patients into distinct molecular subtypes. We used ESTIMATE algorithms to evaluate the immune infiltration. We then applied LASSO Cox regression to establish the TRGs risk model and validated its predictive performance. Results: In this study, we first described the alterations of 42 TRGs in HCC cohorts and characterized the clinicopathological characteristics and tumor microenvironmental landscape of the two distinct subtypes. We then established a tyrosine metabolism-related scoring system and identified five TRGs, which were highly correlated with prognosis and representative of this gene set, namely METTL6, GSTZ1, ADH4, ADH1A, and LCMT1. Patients in the high-risk group had an inferior prognosis. Univariate and multivariate Cox proportional hazards regression analysis also showed that the tyrosine metabolism-related signature was an independent prognostic indicator. Besides, receiver operating characteristic curve (ROC) analysis demonstrated the predictive accuracy of the TRGs signature that could reliably predict 1-, 3-, and 5-year survival in both TCGA and GEO cohorts. We also got consistent results by performing clone formation and invasion analysis, and immunohistochemical (IHC) assays. Moreover, we also discovered that the TRGs signature was significantly associated with the different immune landscapes and therapeutic drug sensitivity. Conclusion: Our comprehensive analysis revealed the potential molecular signature and clinical utilities of TRGs in HCC. The model based on five TRGs can accurately predict the survival outcomes of HCC, improving our knowledge of TRGs in HCC and paving a new path for guiding risk stratification and treatment strategy development for HCC patients.