RESUMO
Cancer-associated fibroblasts (CAFs) play vital roles in establishing a suitable tumor microenvironment. In this study, RNA sequencing data revealed that CAFs could promote cell proliferation, angiogenesis, and ECM reconstitution by binding to integrin families and activating PI3K/AKT pathways in esophageal squamous cell carcinoma (ESCC). The secretions of CAFs play an important role in regulating these biological activities. Among these secretions, we found that MFGE8 is specifically secreted by CAFs in ESCC. Additionally, the secreted MFGE8 protein is essential in CAF-regulated vascularization, tumor proliferation, drug resistance, and metastasis. By binding to Integrin αVß3/αVß5 receptors, MFGE8 promotes tumor progression by activating both the PI3K/AKT and ERK/AKT pathways. Interestingly, the biological function of MFGE8 secreted by CAFs fully demonstrated the major role of CAFs in ESCC and its mode of mechanism, showing that MFGE8 could be a driver factor of CAFs in remodeling the tumor environment. In vivo treatment targeting CAFs-secreting MFGE8 or its receptor produced significant inhibitory effects on ESCC growth and metastasis, which provides an approach for the treatment of ESCC.
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Fibroblastos Associados a Câncer , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/patologia , Fibroblastos Associados a Câncer/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Fibroblastos/metabolismo , Microambiente Tumoral , Antígenos de Superfície/metabolismo , Proteínas do Leite/metabolismoRESUMO
BACKGROUND AND AIMS: Deregulation of adenosine-to-inosine editing by adenosine deaminase acting on RNA 1 (ADAR1) leads to tumor-specific transcriptome diversity with prognostic values for HCC. However, ADAR1 editase-dependent mechanisms governing liver cancer stem cell (LCSC) generation and maintenance have remained elusive. APPROACH AND RESULTS: RNA-seq profiling identified ADAR1-responsive recoding editing events in HCC and showed editing frequency of GLI1 , rather than transcript abundance was clinically relevant. Functional differences in LCSC self-renewal and tumor aggressiveness between wild-type (GLI1 wt ) and edited GLI1 (GLI1 edit ) were elucidated. We showed that overediting of GLI1 induced an arginine-to-glycine (R701G) substitution, augmenting tumor-initiating potential and exhibiting a more aggressive phenotype. GLI1 R701G harbored weak affinity to SUFU, which in turn, promoted its cytoplasmic-to-nuclear translocation to support LCSC self-renewal by increased pluripotency gene expression. Moreover, editing predisposed to stabilize GLI1 by abrogating ß-TrCP-GLI1 interaction. Integrative analysis of single-cell transcriptome further revealed hyperactivated mitophagy in ADAR1-enriched LCSCs. GLI1 editing promoted a metabolic switch to oxidative phosphorylation to control stress and stem-like state through PINK1-Parkin-mediated mitophagy in HCC, thereby conferring exclusive metastatic and sorafenib-resistant capacities. CONCLUSIONS: Our findings demonstrate a novel role of ADAR1 as an active regulator for LCSCs properties through editing GLI1 in the highly heterogeneous HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/patologia , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteínas de Ligação a RNA/metabolismo , Mitofagia , Células-Tronco Neoplásicas/metabolismoRESUMO
OBJECTIVE: Extensive genetic and limited epigenetics have been characterized by the Cancer Genome Atlas (TCGA) among Western High-grade serous ovarian cancer (HGSOC). The present study aimed to characterize Chinese HGSOC at genome scale. METHODS: We used reduced representation bisulfite sequencing to investigate whole-genome and tumor-specific DNA methylation in 21 HGSOC tumors paired with their normal tissues, followed by a replication study involving additional 41 HGSOC patients. Altered methylation patterns in HGSOC were further characterized by gene expression profiles and whole-exome sequencing data. RESULTS: Comparing HGSOC tumors with normal tissues we observed global hypomethylation but with more specific hypermethylation in gene promoter. Totally, we revealed 159,881 differentially methylated regions (DMRs) and 4060 differentially expressed genes (DEGs). By integrating DNA methylation and mRNA expression data, we identified 153 negative (mainly in the upstream region) and 115 positive (mainly in the CDS regions) DMRs-DEGs correlated pairs, respectively. The negatively correlated DMRs-DEGs underlined Wnt and cell adhesion molecule binding as critical canonical pathways disrupted by DNA methylation. Eleven DMRs (in CAPS, FZD7, CDKN2A, PON3, KLF4, etc.), accompanied with a global DNA methylation marker, were validated in the replication samples. Whole-exome sequencing presented a relatively less dominated TP53 mutation in Chinese HGSOC compared to TCGA dataset. Unsupervised analysis of the three-level omics data identified differential methylation and expression subgroups based on tumor genetics, one of which presented increased DNA methylation and significantly associated with TP53 mutation. CONCLUSIONS: Our individual and integrated analyses contribute details about the tissue-specific genetic and DNA methylation landscape of Chinese HGSOC.
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Cistadenocarcinoma Seroso/genética , Metilação de DNA , Neoplasias Ovarianas/genética , Povo Asiático/genética , Cistadenocarcinoma Seroso/patologia , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Genótipo , Humanos , Fator 4 Semelhante a Kruppel , Mutação , Gradação de Tumores , Neoplasias Ovarianas/patologia , Regiões Promotoras Genéticas , Transcriptoma , Proteína Supressora de Tumor p53/genética , Sequenciamento do ExomaRESUMO
Cognitive deficits are closely associated with hippocampal synaptic changes. Phenylethanoid glycosides (PhG), derived from Herba cistanche, are known to exert protective effects on cognitive deficits in Alzheimer's disease (AD); however, the underlying mechanisms of this herbal extract on cognitive performance remain unclear. The aim of this study was thus to examine the protective mechanism attributed to PhG on cognitive deficits in an AD senescence accelerated mouse prone 8 (SAMP8) model. Cognitive deficit parameters examined included (1) Morris water maze (MWM) assessing cognitive performance and (2) quantification of dendritic spine density in hippocampal CA1 region by Golgi staining, a molecular biomarker of synaptic function. In addition, levels of malondialdehyde (MDA) and activities of superoxide dismutase (SOD) and gluthathione peroxidase (GSH-Px) were determined to examine the potential role of oxidant processes in cognitive dysfunction. Data showed that PhG significantly decreased escape latency and path length, associated with a rise in the percentage of time spent in the target quadrant and number of platform crossings. In addition, PhG significantly increased dendritic spine density in the hippocampal CA1 region accompanied by elevated expression levels of synaptophysin (SYN) and post synaptic density 95 (PSD-95), reduced MDA content, and elevated the activities of SOD and GSH-Px. Data suggest that the ability of PhG to ameliorate cognitive deficits in SAMP8 mice may be related to promotion in synaptic plasticity involving antioxidant processes.
Assuntos
Cistanche/química , Cognição/efeitos dos fármacos , Glicosídeos/farmacologia , Oxirredutases/metabolismo , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Animais , Disfunção Cognitiva/tratamento farmacológico , Ativação Enzimática/efeitos dos fármacos , Masculino , CamundongosRESUMO
Synaptic changes are closely associated with cognitive deficits. In addition, testosterone (T) is known to exert regulative effects on synaptic plasticity. T may improve cognitive deficits in Alzheimer's disease (AD) patients, but the underlying mechanisms of androgenic action on cognitive performance remain unclear. The aim of this study was thus to examine the protective mechanism attributed to T on cognitive performance in an AD senescence, accelerated mouse prone 8 (SAMP8) animal model. Using Golgi staining to quantify the dendritic spine density in hippocampal CA1 region, molecular biomarkers of synapse function were analyzed using immunohistochemistry and western blot. T significantly increased the dendritic spine density in hippocampal CA1 region, while flutamide (F) inhibited these T-mediated effects. Immunohistochemistry and western blot analysis showed that the expression levels of brain derived neurotrophic factor (BDNF), postsynaptic density 95 (PSD-95), and p-cyclic-AMP response element binding protein (CREB)/CREB levels were significantly elevated in the T group, but F reduced the T-induced effects in these biomarkers to control levels. There were no significant differences in the expression levels of PSD-95, BDNF, and p-CREB/CREB between C and F. These findings indicate that the effects of T on improvement in synaptic plasticity were mediated via androgen receptor (AR). It is conceivable that new treatments targeted toward preventing synaptic pathology in AD may involve the use of androgen-acting drugs.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Proteína de Ligação a CREB/genética , Expressão Gênica , Guanilato Quinases/genética , Proteínas de Membrana/genética , Plasticidade Neuronal/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Testosterona/metabolismo , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Cognição/efeitos dos fármacos , Proteína 4 Homóloga a Disks-Large , Flutamida/farmacologia , Guanilato Quinases/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Distribuição Aleatória , Testosterona/farmacologiaRESUMO
Cognitive dysfunction is known to be influenced by circulating sex steroidal hormones. The aim of this study was to examine the protective effect and possible protective mechanism of testosterone (T) on cognitive performance in male rats induced by intrahippocampal injections of beta amyloid 1-42 oligomers (Aß1-42). Treatment with T as evidenced by the Morris water maze (MWM) test significantly shortened escape latency and reduced path length to reach the platform compared to the control (C). During probe trials, the T group displayed a significantly greater percent of time in the target quadrant and improved the number of platform crossings compared with C, flutamide (F), an antiandrogen, and a combined F and T group. Flutamide markedly inhibited the influence of T on cognitive performance. Following Nissl staining, the number of intact pyramidal cells was significantly elevated in the T group, and the effect of T was blocked by F. Immunohistochemisty and Western blot analysis showed that the protein expression level of Aß 1-42 was markedly decreased and expression levels of synaptophysin (SYN) significantly increased with T, while F inhibited all T-mediated effects. Our data suggest that the influence of T on cognitive performance was mediated via androgen receptors (AR) to remove beta amyloid, which leads to enhanced synaptic plasticity.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Antagonistas de Androgênios/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Hipocampo/efeitos dos fármacos , Fragmentos de Peptídeos , Testosterona , Doença de Alzheimer/complicações , Animais , Flutamida/farmacologia , Flutamida/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Distribuição Aleatória , Ratos , Sinaptofisina/farmacologia , Sinaptofisina/uso terapêutico , Testosterona/farmacologia , Testosterona/uso terapêuticoRESUMO
Immune checkpoint inhibitors (ICI) transformed the treatment landscape of hepatocellular carcinoma (HCC). Unfortunately, patients with attenuated MHC-I expression remain refractory to ICIs, and druggable targets for upregulating MHC-I are limited. Here, we found that genetic or pharmacologic inhibition of fatty acid synthase (FASN) increased MHC-I levels in HCC cells, promoting antigen presentation and stimulating antigen-specific CD8+ T-cell cytotoxicity. Mechanistically, FASN inhibition reduced palmitoylation of MHC-I that led to its lysosomal degradation. The palmitoyltransferase DHHC3 directly bound MHC-I and negatively regulated MHC-I protein levels. In an orthotopic HCC mouse model, Fasn deficiency enhanced MHC-I levels and promoted cancer cell killing by tumor-infiltrating CD8+ T cells. Moreover, the combination of two different FASN inhibitors, orlistat and TVB-2640, with anti-PD-L1 antibody robustly suppressed tumor growth in vivo. Multiplex IHC of human HCC samples and bioinformatic analysis of The Cancer Genome Atlas data further illustrated that lower expression of FASN was correlated with a higher percentage of cytotoxic CD8+ T cells. The identification of FASN as a negative regulator of MHC-I provides the rationale for combining FASN inhibitors and immunotherapy for treating HCC. SIGNIFICANCE: Inhibition of FASN increases MHC-I protein levels by suppressing its palmitoylation and lysosomal degradation, which stimulates immune activity against hepatocellular carcinoma and enhances the efficacy of immune checkpoint inhibition.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Humanos , Camundongos , Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/genética , Linhagem Celular , Ácido Graxo Sintase Tipo I , Neoplasias Hepáticas/genética , ProteínasRESUMO
OBJECTIVE: To explore the influence of protein arginine methyltransferase 8 (PRMT8) regulating glial cell-derived neurotrophic factor (GDNF) on neuron ferroptosis and macrophage polarization in spinal cord injury (SCI). METHODS: A rat model of SCI was established through an injury induced by an external force. Basso, Beattie, and Bresnahan score, hematoxylin and eosin staining, and immunofluorescence were used, respectively, to detect changes in rat locomotion, spinal cord histopathology, and NeuN expression in the spinal cord. Iron content in the spinal cord and levels of malondialdehyde and glutathione were measured using detection kits. Transmission electron microscopy was used to reveal the morphological characteristics of mitochondria. Western blotting was performed to detect PRMT8, GDNF, cystine/glutamate transporter XCT, glutathione peroxidase 4, 4-hydroxynonenal, heme oxygenase-1, inducible nitric oxide synthase (iNOS), CD16, and arginase 1 (Arg1). The expression levels of iNOS and Arg1 in the spinal cord were visualized by immunofluorescence. ELISA was performed to measure the expression levels of IL-6, IL-1ß, and TNF-α. Rat dorsal root ganglion (DRG) neurons and RMa-bm rat macrophages were treated with lipopolysaccharide under hypoxic conditions. The viability and iron content of the neurons were detected using Cell Counting Kit-8 and a specific probe, respectively. Flow cytometry and immunofluorescence were used to assess macrophage polarization. Chromatin immunoprecipitation was used to identify the binding of PRMT8 to the GDFN promoter. RESULTS: Neuronal ferroptosis and M1 macrophage polarization were promoted, and PRMT8 expression was downregulated in SCI. PRMT8 overexpression exerted therapeutic effects on injured DRG neurons and RMa-bm cells. Moreover, PRMT8 overexpression inhibited ferroptosis and M1 macrophage polarization in rats with SCI. PRMT8 promoted GDNF expression by catalyzing H3K4 methylation. Knockdown of GDNF counteracted the therapeutic effects of PRMT8 overexpression. CONCLUSION: Overexpression of PRMT8 may inhibit ferroptosis and M1 macrophage polarization by increasing GDNF expression, thereby alleviating SCI.
Assuntos
Ferroptose , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Proteína-Arginina N-Metiltransferases , Traumatismos da Medula Espinal , Animais , Ratos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Macrófagos/patologia , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , CitocinasRESUMO
The incidence of bladder cancer and patient survival vary greatly among different populations, but the influence of the associated molecular features and evolutionary processes on its clinical treatment and prognostication remains unknown. Here, we analyze the genomic architectures of 505 bladder cancer patients from Asian/Black/White populations. We identify a previously unknown association between AHNAK mutations and activity of the APOBEC-a mutational signature, the activity of which varied substantially across populations. All significantly mutated genes but only half of arm-level somatic copy number alterations (SCNAs) are enriched with clonal events, indicating large-scale SCNAs as rich sources of bladder cancer clonal diversities. The prevalence of TP53 and ATM clonal mutations as well as the associated burden of SCNAs is significantly higher in Whites/Blacks than in Asians. We identify a trans-ancestry prognostic subtype of bladder cancer characterized by enrichment of non-muscle-invasive patients and muscle-invasive patients with good prognosis, increased CREBBP/FGFR3/HRAS/NFE2L2 mutations, decreased intra-tumor heterogeneity and genome instability, and an activated tumor microenvironment.
Assuntos
Neoplasias da Bexiga Urinária , Humanos , Prognóstico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Mutação/genética , Instabilidade Genômica , Genômica , Microambiente TumoralRESUMO
Lymph node metastasis, the leading cause of mortality in esophageal squamous carcinoma (ESCC) with a highly complex tumor microenvironment, remains underexplored. Here, the transcriptomes of 85 263 single cells are analyzed from four ESCC patients with lymph node metastases. Strikingly, it is observed that the metastatic microenvironment undergoes the emergence or expansion of interferon induced IFIT3+ T, B cells, and immunosuppressive cells such as APOC1+ APOE+ macrophages and myofibroblasts with highly expression of immunoglobulin genes (IGKC) and extracellular matrix component and matrix metallopeptidase genes. A poor-prognostic epithelial-immune dual expression program regulating immune effector processes, whose activity is significantly enhanced in metastatic malignant epithelial cells and enriched in CD74+ CXCR4+ and major histocompatibility complex (MHC) class II genes upregulated malignant epithelia cells is discovered. Comparing with primary tumor, differential intercellular communications of metastatic ESCC microenvironment are revealed and furtherly validated via multiplexed immunofluorescence and immunohistochemistry staining, which mainly rely on the crosstalk of APOC1+ APOE+ macrophages with tumor and stromal cell. The data highlight potential molecular mechanisms that shape the lymph-node metastatic microenvironment and may inform drug discovery and the development of new strategies to target these prometastatic nontumor components for inhibiting tumor growth and overcoming metastasis to improve clinical outcomes.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Transcriptoma/genética , Ecossistema , Apolipoproteínas E/genética , Microambiente Tumoral/genéticaRESUMO
Despite the intense CD8+ T-cell infiltration in the tumor microenvironment of nasopharyngeal carcinoma, anti-PD-1 immunotherapy shows an unsatisfactory response rate in clinical trials, hindered by immunosuppressive signals. To understand how microenvironmental characteristics alter immune homeostasis and limit immunotherapy efficacy in nasopharyngeal carcinoma, here we establish a multi-center single-cell cohort based on public data, containing 357,206 cells from 50 patient samples. We reveal that nasopharyngeal carcinoma cells enhance development and suppressive activity of regulatory T cells via CD70-CD27 interaction. CD70 blocking reverts Treg-mediated suppression and thus reinvigorate CD8+ T-cell immunity. Anti-CD70+ anti-PD-1 therapy is evaluated in xenograft-derived organoids and humanized mice, exhibiting an improved tumor-killing efficacy. Mechanistically, CD70 knockout inhibits a collective lipid signaling network in CD4+ naïve and regulatory T cells involving mitochondrial integrity, cholesterol homeostasis, and fatty acid metabolism. Furthermore, ATAC-Seq delineates that CD70 is transcriptionally upregulated by NFKB2 via an Epstein-Barr virus-dependent epigenetic modification. Our findings identify CD70+ nasopharyngeal carcinoma cells as a metabolic switch that enforces the lipid-driven development, functional specialization and homeostasis of Tregs, leading to immune evasion. This study also demonstrates that CD70 blockade can act synergistically with anti-PD-1 treatment to reinvigorate T-cell immunity against nasopharyngeal carcinoma.
Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Animais , Camundongos , Linfócitos T Reguladores , Carcinoma Nasofaríngeo/genética , Ligante CD27/genética , Ligante CD27/metabolismo , Herpesvirus Humano 4/metabolismo , Neoplasias Nasofaríngeas/genética , Lipídeos , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Microambiente TumoralRESUMO
Background: The aim of this study was to investigate the feasibility of using a novel neuromuscular electrical stimulation (NMES) device for enhanced recovery after total hip replacement surgery. Methods: Sixty patients undergoing total hip replacement for osteoarthritis of the hip were randomized and divided into 2 groups: 1 group received postoperative treatment with the NMES device, and the other group did not receive NMES. The primary outcome measures were postoperative pain, lower limb swelling, and length of stay (LOS) postsurgery. Secondary outcomes included wound drainage at 24 hours and acceptability by the intervention of the device. Results: Data from 60 participants were analyzed (NMES (n = 30), control group (n = 30)). Patients in the NMES group demonstrated a general trend of beneficial postoperative pain, calf swelling, and average length of stay from postoperative to discharge. However, wound drainage largely remained static for both groups. The overall comfort rate of the device was 93.3%. Conclusions: The results of this study suggest that the gekoTM NMES device is partly useful for enhanced recovery after total hip replacement surgery. In addition, the device should be considered tolerable and safe. A larger study is required with this device in the future to determine its effectiveness on compelling data.
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BACKGROUND: Lymph node metastasis is one of most common determinants of the stage and prognosis of gastric cancer (GC). However, the key molecular events and mechanisms mediating lymph node metastasis remain elusive. METHODS: RNA sequencing was used to identify driver genes responsible for lymph node metastasis in four cases of gastric primary tumors, metastatic lesions of lymph nodes and matched normal gastric epithelial tissue. qRT-PCR and IHC were applied to examine RPRD1B expression. Metastatic functions were evaluated in vitro and in vivo. RNA-seq was used to identify target genes. ChIP, EMSA and dual luciferase reporter assays were conducted to identify the binding sites of target genes. Co-IP, RIP, MeRIP, RNA-FISH and ubiquitin assays were applied to explore the underlying mechanisms. RESULTS: The top 8 target genes (RPRD1B, MAP4K4, MCM2, TOPBP1, FRMD8, KBTBD2, ADAM10 and CXCR4) that were significantly upregulated in metastatic lymph nodes of individuals with GC were screened. The transcriptional cofactor RPRD1B (regulation of nuclear pre-mRNA domain containing 1B) was selected for further characterization. The clinical analysis showed that RPRD1B was significantly overexpressed in metastatic lymph nodes and associated with poor outcomes in patients with GC. The Mettl3-induced m6A modification was involved in the upregulation of RPRD1B. Functionally, RPRD1B promoted lymph node metastasis capabilities in vitro and in vivo. Mechanistic studies indicated that RPRD1B increased fatty acid uptake and synthesis by transcriptionally upregulating c-Jun/c-Fos and activating the c-Jun/c-Fos/SREBP1 axis. In addition, NEAT1 was upregulated significantly by c-Jun/c-Fos in RPRD1B-overexpressing cells. NEAT1, in turn, increased the stability of the RPRD1B mRNA by recruiting the m6A "reader" protein hnRNPA2B1 and reduced the degradation of the RPRD1B protein by inhibiting TRIM25-mediated ubiquitination. Notably, this functional circuitry was disrupted by an inhibitor of c-Jun/c-Fos/AP1 proteins (SR11302) and small interfering RNAs targeting NEAT1, leading to a preferential impairment of lymph node metastasis. CONCLUSIONS: Based on these findings, RPRD1B facilitated FA metabolism and assisted primary tumor implantation in lymph nodes via the c-Jun/c-Fos/SREBP1 axis, which was enhanced by a NEAT1-mediated positive feedback loop, serving as a potential therapeutic target for GC treatment.
Assuntos
RNA Longo não Codificante , Neoplasias Gástricas , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Ácidos Graxos , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metástase Linfática , Metiltransferases/metabolismo , Proteínas de Neoplasias , Proteínas Serina-Treonina Quinases , Precursores de RNA , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Neoplasias Gástricas/patologia , Ubiquitinas/metabolismoRESUMO
The overall survival rate of gliomas has not significantly improved despite new effective treatments, mainly due to tumor heterogeneity and drug delivery. Here, we perform an integrated clinic-genomic analysis of 1, 477 glioma patients from a Chinese cohort and a TCGA cohort and propose a potential prognostic model for gliomas. We identify that SBS11 and SBS23 mutational signatures are associated with glioma recurrence and indicate worse prognosis only in low-grade type of gliomas and IDH-Mut subtype. We also identify 42 genomic features associated with distinct clinical outcome and successfully used ten of these to develop a prognostic risk model of gliomas. The high-risk glioma patients with shortened survival were characterized by high level of frequent copy number alterations including PTEN, CDKN2A/B deletion, EGFR amplification, less IDH1 or CIC gene mutations, high infiltration levels of immunosuppressive cells and activation of G2M checkpoint and Oxidative phosphorylation oncogenic pathway.
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BACKGROUND: Previous in vitro hepatocyte differentiation model showed that TROY was specifically expressed in liver progenitor cells and a small proportion of hepatocellular carcinoma cells, suggesting that TROY may participate in hepatocellular carcinoma (HCC) stemness regulation. Here, we aim to investigate the role and mechanism of TROY in HCC pathogenesis. METHOD: Bioinformatics analysis of the TCGA dataset has been used to identify the function and mechanism of TROY. Spheroid, apoptosis, and ALDH assay were performed to evaluate the stemness functions. Validation of the downstream pathway was based on Western blot, co-immunoprecipitation, and double immunofluorescence. RESULTS: HCC tissue microarray study found that a high frequency of TROY-positive cells was detected in 53/130 (40.8%) of HCC cases, which was significantly associated with poor prognosis and tumor metastasis. Functional studies revealed that TROY could promote self-renewal, drug resistance, tumorigenicity, and metastasis of HCC cells. Mechanism study found that TROY could interact with PI3K subunit p85α, inducing its polyubiquitylation and degradation. The degradation of p85α subsequently activate PI3K/AKT/TBX3 signaling and upregulated pluripotent genes expression including SOX2, NANOG, and OCT4, and promoted EMT in HCC cells. Interestingly, immune cell infiltration analysis found that upregulation of TROY in HCC tissues was induced by TGF-ß1 secreted from CAFs. PI3K inhibitor wortmannin could effectively impair tumor stemness to sorafenib. CONCLUSION: We demonstrated that TROY is an HCC CSC marker and plays an important role in HCC stemness regulation. Targeting TROY-positive CSCs with PI3K inhibitor wortmannin combined with chemo- or targeted drugs might be a novel therapeutic strategy for HCC patients.
Assuntos
Carcinoma Hepatocelular , Classe Ia de Fosfatidilinositol 3-Quinase , Neoplasias Hepáticas , Células-Tronco Neoplásicas , Proteínas Proto-Oncogênicas c-akt , Receptores do Fator de Necrose Tumoral , Proteínas com Domínio T , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Terapia de Alvo Molecular , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas com Domínio T/metabolismo , Wortmanina/farmacologiaRESUMO
The tumor microenvironment (TME) of nasopharyngeal carcinoma (NPC) harbors a heterogeneous and dynamic stromal population. A comprehensive understanding of this tumor-specific ecosystem is necessary to enhance cancer diagnosis, therapeutics, and prognosis. However, recent advances based on bulk RNA sequencing remain insufficient to construct an in-depth landscape of infiltrating stromal cells in NPC. Here we apply single-cell RNA sequencing to 66,627 cells from 14 patients, integrated with clonotype identification on T and B cells. We identify and characterize five major stromal clusters and 36 distinct subpopulations based on genetic profiling. By comparing with the infiltrating cells in the non-malignant microenvironment, we report highly representative features in the TME, including phenotypic abundance, genetic alternations, immune dynamics, clonal expansion, developmental trajectory, and molecular interactions that profoundly influence patient prognosis and therapeutic outcome. The key findings are further independently validated in two single-cell RNA sequencing cohorts and two bulk RNA-sequencing cohorts. In the present study, we reveal the correlation between NPC-specific characteristics and progression-free survival. Together, these data facilitate the understanding of the stromal landscape and immune dynamics in NPC patients and provides deeper insights into the development of prognostic biomarkers and therapeutic targets in the TME.
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Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Microambiente Tumoral/fisiologia , Linfócitos B , Fibroblastos , Regulação Neoplásica da Expressão Gênica , Humanos , Células Mieloides , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/imunologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/imunologia , Fenótipo , Prognóstico , Intervalo Livre de Progressão , Análise de Sequência de RNA , Células Estromais , Linfócitos T , Microambiente Tumoral/imunologiaRESUMO
The genetic landscape of clear cell renal cell carcinoma (ccRCC) had been investigated extensively but its evolution patterns remained unclear. Here we analyze the clonal architectures of 473 patients from three different populations. We find that the mutational signatures vary substantially across different populations and evolution stages. The evolution patterns of ccRCC have great inter-patient heterogeneities, with del(3p) being regarded as the common earliest event followed by three early departure points: VHL and PBRM1 mutations, del(14q) and other somatic copy number alterations (SCNAs) including amp(7), del(1p) and del(6q). We identify three prognostic subtypes of ccRCC with distinct clonal architectures and immune infiltrates: long-lived patients, enriched with VHL but depleted of BAP1 mutations, have high levels of Th17 and CD8+ T cells while short-lived patients with high burden of SCNAs have high levels of Tregs and Th2 cells, highlighting the importance of evaluating evolution patterns in the clinical management of ccRCC.