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Hypoxia is a key feature of tumor microenvironment that contributes to the development of breast cancer stem cells (BCSCs) with strong self-renewal properties. However, the specific mechanism underlying hypoxia in BCSC induction is not completely understood. Herein, we provide evidence that a novel hypoxia-specific circSTT3A is significantly upregulated in clinical breast cancer (BC) tissues, and is closely related to the clinical stage and poor prognosis of patients with BC. The study revealed that hypoxia-inducible factor 1 alpha (HIF1α)-regulated circSTT3A has a remarkable effect on mammosphere formation in breast cancer cells. Mechanistically, circSTT3A directly interacts with nucleotide-binding domain of heat shock protein 70 (HSP70), thereby facilitating the recruitment of phosphoglycerate kinase 1 (PGK1) via its substrate-binding domain, which reduces the ubiquitination and increases the stability of PGK1. The enhanced levels of PGK1 catalyze 1,3-diphosphoglycerate (1,3-BPG) into 3-phosphoglycerate (3-PG) leading to 3-PG accumulation and increased serine synthesis, S-adenosylmethionine (SAM) accumulation, and trimethylation of histone H3 lysine 4 (H3K4me3). The activation of the H3K4me3 contributes to BCSCs by increasing the transcriptional level of stemness-related factors. Especially, our work reveals that either loss of circSTT3A or PGK1 substantially suppresses tumor initiation and tumor growth, which dramatically increases the sensitivity of tumors to doxorubicin (DOX) in mice. Injection of PGK1-silenced spheroids with 3-PG can significantly reverse tumor initiation and growth in mice, thereby increasing tumor resistance to DOX. In conclusion, our study sheds light on the functional role of hypoxia in the maintenance of BCSCs via circSTT3A/HSP70/PGK1-mediated serine synthesis, which provides new insights into metabolic reprogramming, tumor initiation and growth. Our findings suggest that targeting circSTT3A alone or in combination with chemotherapy has potential clinical value for BC management.
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Neoplasias da Mama , Humanos , Camundongos , Animais , Feminino , Neoplasias da Mama/metabolismo , Histonas/metabolismo , Hipóxia/metabolismo , Transformação Celular Neoplásica/metabolismo , Células-Tronco Neoplásicas/patologia , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Bayesian methods that utilize Bayes' theorem to update the knowledge of desired parameters after each measurement are used in a wide range of quantum science. For various applications in quantum science, efficiently and accurately achieving a quantum transition frequency is essential. However, the exact relation between a desired transition frequency and the controllable experimental parameters is usually absent. Here, we propose an efficient scheme to search the suitable conditions for a desired magneto-sensitive transition via an adaptive Bayesian algorithm and experimentally demonstrate it by using coherent population trapping in an ensemble of laser-cooled 87Rb atoms. The transition frequency is controlled by an external magnetic field, which can be tuned in realtime by applying a d.c. voltage. Through an adaptive Bayesian algorithm, the voltage can automatically converge to the desired one from a random initial value only after few iterations (N ≥ 10). The response time is limited by the time of obtaining the spectrum signal, which is about 50 s for 10 iterations in our experiment. In particular, when the relation between the target frequency and the applied voltage is nonlinear (e.g., quadratic), our algorithm shows significant advantages over traditional methods. This work provides a simple and efficient way to determine a transition frequency, which can be widely applied in the fields of precision spectroscopy, such as atomic clocks, magnetometers, and nuclear magnetic resonance.
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We demonstrate a bichromatic Doppler-free spectroscopy of an 87RbD1 line by using a dual-frequency, counterpropagating laser field with orthogonal linear polarizations. A reversed Doppler-free resonance dip is observed in the dual-frequency scheme, and a significant improvement of frequency discrimination curve is acquired due to the coherent population trapping (CPT) effect. The influence of the static magnetic field and laser intensity on the spectroscopy is studied in both single- and dual-frequency schemes. After locking the laser frequency to the 87RbD1 line in the dual-frequency stabilization scheme, the beat note fractional frequency stability is at the level of 7×10-12 at 1 s integration time. This technique can be used in various applications, such as CPT atomic clocks, laser spectroscopy, quantum optics, and laser-cooling experiments.
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Background: Coatomer protein complex zeta 2 (COPZ2) is a member of heptameric coatomer protein complex I and has been reported to be involved in various tumors. However, COPZ2's potential involvement in glioma remains to be explored. Methods: The COPZ2 expression and related clinical data were obtained from The Cancer Genome Atlas (TCGA). TIMER2.0 and the Ualcan database were utilized to assess the COPZ2 expression in various tumors. Univariable, multivariate Cox regression, Kaplan-Meier methods, nomogram analysis, and ROC curve analysis were carried out to assess the relationship of COPZ2 and other prognostic factors with glioma. The LinkedOmics database was used to predict the potential biological mechanism of COPZ2 in glioma. We also conducted in vitro experiments to evaluate the functional role and mechanism of COPZ2 in glioma cell lines. Results: We found that COPZ2 was highly expressed in glioma and it was associated with age and WHO grades. Kaplan-Meier survival curves, Cox analysis, nomogram analysis, and ROC curve showed that COPZ2 was a disadvantageous factor in poor glioma prognosis. The functions of COPZ2 and co-expression genes were significantly associated with neutrophil-mediated immunity, granulocyte activation, and response to interferon-gamma. In addition, COPZ2 knockdown significantly inhibited the proliferation, migration, and invasion of glioblastoma cells. Mechanistically, COPZ2 suppressed tumor development by participating in the regulation of the PI3K-AKT signaling pathway. Conclusion: Our results demonstrated that the elevation of COPZ2 was associated with the prognosis and progression of glioma, and it might be a potential diagnostic and prognostic biomarker for glioma.
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Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and has a poor prognosis and a high propensity to metastasize. Lipid metabolism has emerged as a critical regulator of tumor progression and metastasis in other cancer types. Characterization of the lipid metabolic features of TNBC could provide important insights into the drivers of TNBC metastasis. Here, we showed that metastatic TNBC tumors harbor more unsaturated phospholipids, especially long-chain polyunsaturated fatty acids, at the sn-2 position of phosphatidylcholine and phosphatidylethanolamine compared with primary tumors. Metastatic TNBC tumors upregulated ACSL4, a long-chain polyunsaturated acyl-CoA synthetase that drives the preferential incorporation of polyunsaturated fatty acids into phospholipids, resulting in the alteration of membrane phospholipid composition and properties. Moreover, ACSL4-mediated phospholipid remodeling of the cell membrane induced lipid-raft localization and activation of integrin ß1 in a CD47-dependent manner, which led to downstream focal adhesion kinase phosphorylation that promoted metastasis. Importantly, pharmacologic inhibition of ACSL4 suppressed tumor growth and metastasis and increased chemosensitivity in TNBC models in vivo. These findings indicate that ACSL4-mediated phospholipid remodeling enables TNBC metastasis and can be inhibited as a potential strategy to improve the efficacy of chemotherapy in TNBC. SIGNIFICANCE: ACSL4 upregulation in triple-negative breast cancer alters cell membrane phospholipid composition to increase integrin ß1 activation and drive metastasis, indicating that targeting ACSL4 could potentially block metastasis and improve patient outcomes.
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Coenzima A Ligases , Integrina beta1 , Fosfolipídeos , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Humanos , Feminino , Animais , Coenzima A Ligases/metabolismo , Camundongos , Integrina beta1/metabolismo , Fosfolipídeos/metabolismo , Linhagem Celular Tumoral , Metástase Neoplásica , Membrana Celular/metabolismo , Camundongos Nus , Proliferação de CélulasRESUMO
This study is aimed at investigating the correlations of PCSK9 and LDLR gene polymorphisms as well as serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels with atherosclerosis and lipid metabolism in patients on maintenance hemodialysis (HD). A single nucleotide polymorphism at the E670G locus of the PCSK9 gene and the rs688 locus of the LDLR gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism. All study subjects' blood lipid (triglyceride [TG], total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol [LDL-C]) concentrations and lipoprotein(a) and PCSK9 levels were measured. The differences in blood lipid levels between different genotypes of the E670G locus of the PCSK9 gene and the rs688 locus of the LDLR gene in patients on maintenance HD with atherosclerosis were compared. Patients on maintenance HD with atherosclerosis at the E670G locus of the PCSK9 gene AG + GG genotype had higher levels of TG, TC, LDL-C, and lipoprotein(a) than the AA genotype, and lower levels of HDL-C than the AA genotype. Patients on maintenance HD with atherosclerosis at the rs688 locus of the LDLR gene CT + TT genotype had higher levels of TG, TC, LDL-C, and lipoprotein(a) than the CC genotype, and lower levels of HDL-C than the CC genotype. Serum PCSK9 contents in patients on maintenance HD with atherosclerosis were positively correlated with lipid indices (TG, TC, LDL-C, and lipoprotein(a)) and carotid ultrasound indices (intima-media thickness and resistance index), and negatively correlated with HDL-C, maximum systolic blood flow velocity, and minimum diastolic blood flow velocity (all P < .05).
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Aterosclerose , Pró-Proteína Convertase 9 , Humanos , Pró-Proteína Convertase 9/genética , LDL-Colesterol , Metabolismo dos Lipídeos/genética , Espessura Intima-Media Carotídea , Aterosclerose/genética , Polimorfismo de Nucleotídeo Único , Lipídeos , Triglicerídeos , HDL-Colesterol , Diálise Renal , Lipoproteína(a)/genética , Lipoproteína(a)/metabolismoRESUMO
Background: End-stage renal disease is primarily caused by diabetic kidney disease (DKD). The Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, has anti-inflammatory, lipid-lowering and hypoglycemic properties. It also inhibits renal fibrosis. Although its physiological role is not fully understood, it also plays a role in the control of diabetic nephropathy (DN). Methods: In the present study, we examined male FXR & leptin receptor double knockout mice, in which weight, blood glucose, body fat, and other indicators were monitored. After 6 months of rearing, blood and urine samples were collected and biochemical parameters were measured. Fibrosis was assessed by Masson's stain, while the assessment of the resuscitation case's condition was performed using succinate dehydrogenase (SDHA) stain immunohistochemistry, which measures aerobic respiration. Expression of molecules such as connective tissue growth factor (CTGF), SMAD family members 3 (Smad3) and 7 (Smad7), and small heterodimer partner were detected by RT-PCR and Western blotting as part of the application. Results: FXR knockout decreased body weight and body fat in db/db mice, but increased blood glucose, urine output, and renal fibrosis. Primary mesangial cells (P-MCs) from FXR+/ + mice stimulated with transforming growth factor ß1 (TGFß1) showed significantly higher levels of related fibrosis factors, TGFß1 and Smad3 mRNA and protein, and significantly reduced levels of Smad7. These effects were reversed by the action of FXR agonist chenodeoxycholic acid (CDCA). P-MCs from FXR-/ - mice stimulated with TGFß1 resulted in an increase in the expression and protein levels of collagen I and TGFß1, and the addition of CDCA had no significant effect on TGFß1 stimulation. However, compared with FXR+/ +db/db mice, the rate of oxygen consumption, the rate of carbon dioxide production, and the rate of energy conversion were increased in FXR-/ -db/db mice, whereas the SDHA succinate dehydrogenase, a marker enzyme for aerobic respiration, was significantly decreased. Conclusions: These results provide evidence that FXR plays a critical role in the regulation of mesangial cells in DN. The likely mechanism is that aberrant FXR expression activates TGFß1, which induces extracellular matrix accumulation through the classical Smad signaling pathway, leading to mitochondrial dysfunction.
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Nefropatias Diabéticas , Succinato Desidrogenase , Animais , Masculino , Camundongos , Glicemia/metabolismo , Ácido Quenodesoxicólico/metabolismo , Nefropatias Diabéticas/metabolismo , Fibrose , Glucose/metabolismo , Rim/metabolismo , Camundongos Endogâmicos , Succinato Desidrogenase/metabolismoRESUMO
Cancer-associated fibroblasts (CAFs) are the predominant stromal cells in the microenvironment and play important roles in tumor progression, including chemoresistance. However, the response of CAFs to chemotherapeutics and their effects on chemotherapeutic outcomes are largely unknown. In this study, we showed that epirubicin (EPI) treatment triggered ROS which initiated autophagy in CAFs, TCF12 inhibited autophagy flux and further promoted exosome secretion. Inhibition of EPI-induced reactive oxygen species (ROS) production with N-acetyl-L-cysteine (NAC) or suppression of autophagic initiation with short interfering RNA (siRNA) against ATG5 blunted exosome release from CAFs. Furthermore, exosome secreted from EPI-treated CAFs not only prevented ROS accumulation in CAFs but also upregulated the CXCR4 and c-Myc protein levels in recipient ER+ breast cancer cells, thus promoting EPI resistance of tumor cells. Together, the current study provides novel insights into the role of stressed CAFs in promoting tumor chemoresistance and reveal a new function of TCF12 in regulating autophagy impairment and exosome release.
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Neoplasias da Mama , Fibroblastos Associados a Câncer , Exossomos , Humanos , Feminino , Fibroblastos Associados a Câncer/patologia , Neoplasias da Mama/patologia , Epirubicina/farmacologia , Epirubicina/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fibroblastos/metabolismo , Exossomos/metabolismo , Microambiente Tumoral , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismoRESUMO
Viral tracers that enable efficient retrograde labeling of projection neurons are powerful vehicles for structural and functional dissections of the neural circuit and for the treatment of brain diseases. Currently, some recombinant adeno-associated viruses (rAAVs) based on capsid engineering are widely used for retrograde tracing, but display undesirable brain area selectivity due to inefficient retrograde transduction in certain neural connections. Here we developed an easily editable toolkit to produce high titer AAV11 and demonstrated that it exhibits potent and stringent retrograde labeling of projection neurons in adult male wild-type or Cre transgenic mice. AAV11 can function as a powerful retrograde viral tracer complementary to AAV2-retro in multiple neural connections. In combination with fiber photometry, AAV11 can be used to monitor neuronal activities in the functional network by retrograde delivering calcium-sensitive indicator under the control of a neuron-specific promoter or the Cre-lox system. Furthermore, we showed that GfaABC1D promoter embedding AAV11 is superior to AAV8 and AAV5 in astrocytic tropism in vivo, combined with bidirectional multi-vector axoastrocytic labeling, AAV11 can be used to study neuron-astrocyte connection. Finally, we showed that AAV11 allows for analyzing circuit connectivity difference in the brains of the Alzheimer's disease and control mice. These properties make AAV11 a promising tool for mapping and manipulating neural circuits and for gene therapy of some neurological and neurodegenerative disorders.
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Astrócitos , Neurônios , Camundongos , Masculino , Animais , Camundongos Transgênicos , Interneurônios , Encéfalo , Dependovirus/genética , Vetores Genéticos/genéticaRESUMO
BACKGROUND: More than 90% of the mortality of triple-negative breast cancer (TNBC) patients is attributed to cancer metastasis with organotropism. The lung is a frequent site of TNBC metastasis. However, the precise molecular mechanism for lung-specific metastasis of TNBC is not well understood. METHODS: RNA sequencing was performed to identify patterns of gene expression associated with lung metastatic behavior using 4T1-LM3, MBA-MB-231-LM3, and their parental cells (4T1-P, MBA-MB-231-P). Expressions of RGCC, called regulator of cell cycle or response gene to complement 32 protein, were detected in TNBC cells and tissues by qRT-PCR, western blotting, and immunohistochemistry. Kinase activity assay was performed to evaluate PLK1 kinase activity. The amount of phosphorylated AMP-activated protein kinase α2 (AMPKα2) was detected by immunoblotting. RGCC-mediated metabolism was determined by UHPLC system. Oxidative phosphorylation was evaluated by JC-1 staining and oxygen consumption rate (OCR) assay. Fatty acid oxidation assay was conducted to measure the status of RGCC-mediated fatty acid oxidation. NADPH and ROS levels were detected by well-established assays. The chemical sensitivity of cells was evaluated by CCK8 assay. RESULTS: RGCC is aberrantly upregulated in pulmonary metastatic cells. High level of RGCC is significantly related with lung metastasis in comparison with other organ metastases. RGCC can effectively promote kinase activity of PLK1, and the activated PLK1 phosphorylates AMPKα2 to facilitate TNBC lung metastasis. Mechanistically, the RGCC/PLK1/AMPKα2 signal axis increases oxidative phosphorylation of mitochondria to generate more energy, and promotes fatty acid oxidation to produce abundant NADPH. These metabolic changes contribute to sustaining redox homeostasis and preventing excessive accumulation of potentially detrimental ROS in metastatic tumor cells, thereby supporting TNBC cell survival and colonization during metastases. Importantly, targeting RGCC in combination with paclitaxel/carboplatin effectively suppresses pulmonary TNBC lung metastasis in a mouse model. CONCLUSIONS: RGCC overexpression is significantly associated with lung-specific metastasis of TNBC. RGCC activates AMPKα2 and downstream signaling through RGCC-driven PLK1 activity to facilitate TNBC lung metastasis. The study provides implications for RGCC-driven OXPHOS and fatty acid oxidation as important therapeutic targets for TNBC treatment.
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Neoplasias Pulmonares , Neoplasias de Mama Triplo Negativas , Animais , Camundongos , Humanos , Neoplasias de Mama Triplo Negativas/genética , Linhagem Celular Tumoral , Fosforilação Oxidativa , NADP/metabolismo , NADP/farmacologia , NADP/uso terapêutico , Espécies Reativas de Oxigênio , Neoplasias Pulmonares/metabolismo , Ácidos Graxos/metabolismo , Proliferação de CélulasRESUMO
[This corrects the article DOI: 10.7150/thno.55074.].
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Tumor initiation, development, and relapse may be closely associated with cancer stem cells (CSCs). The complicated mechanisms underlying the maintenance of CSCs are keeping in illustration. Long noncoding RNAs (lncRNAs), due to their multifunction in various biological processes, have been indicated to play a crucial role in CSC renewal and stemness maintenance. Using lncRNA array, we identified a novel lncRNA (named lnc408) in epithelial-mesenchymal transition-related breast CSCs (BCSCs). The lnc408 is high expressed in BCSCs in vitro and in vivo. The enhanced lnc408 is critical to BCSC characteristics and tumorigenesis. Lnc408 can recruit transcript factor SP3 to CBY1 promoter to serve as an inhibitor in CBY1 transcription in BCSCs. The high expressed CBY1 in non-BCSC interacts with 14-3-3 and ß-catenin to form a ternary complex, which leads a translocation of the ternary complex into cytoplasm from nucleus and degradation of ß-catenin in phosphorylation-dependent pattern. The lnc408-mediated decrease of CBY1 in BCSCs impairs the formation of 14-3-3/ß-catenin/CBY1 complex, and keeps ß-catenin in nucleus to promote CSC-associated CD44, SOX2, Nanog, Klf4, and c-Myc expressions and contributes to mammosphere formation; however, restoration of CBY1 expression in tumor cells reduces BCSC and its enrichment, thus lnc408 plays an essential role in maintenance of BCSC stemness. In shortly, these findings highlight that the novel lnc408 functions as an oncogenic factor by recruiting SP3 to inhibit CBY1 expression and ß-catenin accumulation in nucleus to maintain stemness properties of BCSCs. Lnc408-CBY1-ß-catenin signaling axis might serve as a new diagnostic and therapeutic target for breast cancer.
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Neoplasias da Mama/metabolismo , Proteínas de Transporte/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Nucleares/metabolismo , Fator de Transcrição Sp3/metabolismo , beta Catenina/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Xenoenxertos , Humanos , Fator 4 Semelhante a Kruppel , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/patologiaRESUMO
Invasion and metastasis are the leading causes of death in patients with breast cancer (BC), and epithelial-mesenchymal transformation (EMT) plays an essential role in this process. Here, we found that Lnc-408, a novel long noncoding RNA (lncRNA), is significantly upregulated in BC cells undergoing EMT and in BC tumor with lymphatic metastases compared with those without lymphatic metastases. Lnc-408 can enhance BC invasion and metastasis by regulating the expression of LIMK1. Mechanistically, Lnc-408 serves as a sponge for miR-654-5p to relieve the suppression of miR-654-5p on its target LIMK1. Knockdown or knockout of Lnc-408 in invasive BC cells clearly decreased LIMK1 levels, and ectopic Lnc-408 in MCF-7 cells increased LIMK1 expression to promote cell invasion. Lnc-408-mediated enhancement of LIMK1 plays a key role in cytoskeletal stability and promotes invadopodium formation in BC cells via p-cofilin/F-actin. In addition, the increased LIMK1 also facilitates the expression of MMP2, ITGB1, and COL1A1 by phosphorylating CREB. In conclusion, our findings reveal that Lnc-408 promotes BC invasion and metastasis via the Lnc-408/miR-654-5p/LIMK1 axis, highlighting a novel promising target for the diagnosis and treatment of BC.
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Neoplasias da Mama/genética , Movimento Celular/genética , Quinases Lim/genética , Metástase Neoplásica/genética , RNA Longo não Codificante/genética , Apoptose/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , MicroRNAs/genética , Metástase Neoplásica/patologia , Regulação para Cima/genéticaRESUMO
Cancer-associated fibroblasts (CAFs), a predominant component of the tumor microenvironment, contribute to aggressive angiogenesis progression. In clinical practice, traditional anti-angiogenic therapy, mainly anti-VEGF, provides extremely limited beneficial effects to breast cancer. Here, we reveal that FOS-like 2 (FOSL2), a transcription factor in breast CAFs, plays a critical role in VEGF-independent angiogenesis in stromal fibroblasts. Methods: FOSL2 and Wnt5a expression was assessed by qRT-PCR, western blotting and immunohistochemistry in primary and immortalized CAFs and clinical samples. FOSL2- or Wnt5a-silenced CAFs and FOSL2-overexpressing NFs were established to explore their proangiogenic effects. Invasion, tubule formation, three-dimensional sprouting assays, and orthotopic xenografts were conducted as angiogenesis experiments. FZD5/NF-κB/ERK signaling activation was evaluated by western blotting after blocking VEGF/VEGFR with an anti-VEGF antibody and axitinib. Dual luciferase reporter assays and chromatin immunoprecipitation were performed to test the role of FOSL2 in regulating Wnt5a expression, and Wnt5a in the serum of the patients was measured to assess its clinical diagnostic value for breast cancer patients. Results: Enhanced FOSL2 in breast CAFs was significantly associated with angiogenesis and clinical progression in patients. The supernatant from CAFs highly expressing FOSL2 strongly promoted tube formation and sprouting of human umbilical vein endothelial cells (HUVECs) in a VEGF-independent manner and angiogenesis as well as tumor growth in vivo. Mechanistically, the enhanced FOSL2 in CAFs was regulated by estrogen/cAMP/PKA signaling. Wnt5a, a direct target of FOSL2, specifically activated FZD5/NF-κB/ERK signaling in HUVECs to promote VEGF-independent angiogenesis. In addition, a high level of Wnt5a was commonly detected in the serum of breast cancer patients and closely correlated with microvessel density in breast tumor tissues, suggesting a promising clinical value of Wnt5a for breast cancer diagnostics. Conclusion: FOSL2/Wnt5a signaling plays an essential role in breast cancer angiogenesis in a VEGF-independent manner, and targeting the FOSL2/Wnt5a signaling axis in CAFs may offer a potential option for antiangiogenesis therapy.
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Neoplasias da Mama/genética , Fibroblastos Associados a Câncer/metabolismo , Carcinoma/genética , Antígeno 2 Relacionado a Fos/genética , Neovascularização Patológica/genética , Proteína Wnt-5a/genética , Animais , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/metabolismo , Carcinoma/irrigação sanguínea , Carcinoma/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Ativação Transcricional/genética , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The hostile hypoxic microenvironment takes primary responsibility for the rapid expansion of breast cancer tumors. However, the underlying mechanism is not fully understood. Here, using RNA sequencing (RNA-seq) analysis, we identified a hypoxia-induced long noncoding RNA (lncRNA) KB-1980E6.3, which is aberrantly upregulated in clinical breast cancer tissues and closely correlated with poor prognosis of breast cancer patients. The enhanced lncRNA KB-1980E6.3 facilitates breast cancer stem cells (BCSCs) self-renewal and tumorigenesis under hypoxic microenvironment both in vitro and in vivo. Mechanistically, lncRNA KB-1980E6.3 recruited insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) to form a lncRNA KB-1980E6.3/IGF2BP1/c-Myc signaling axis that retained the stability of c-Myc mRNA through increasing binding of IGF2BP1 with m6A-modified c-Myc coding region instability determinant (CRD) mRNA. In conclusion, we confirm that lncRNA KB-1980E6.3 maintains the stemness of BCSCs through lncRNA KB-1980E6.3/IGF2BP1/c-Myc axis and suggest that disrupting this axis might provide a new therapeutic target for refractory hypoxic tumors.
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Neoplasias da Mama/genética , Carcinogênese/genética , Proteínas Proto-Oncogênicas c-myc/genética , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Autorrenovação Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células-Tronco Neoplásicas/metabolismo , Estabilidade de RNA/genética , RNA Mensageiro/genéticaRESUMO
Mismatch negativity (MMN) is suitable for studies of preattentive auditory discriminability and the auditory memory trace. Subjective cognitive decline (SCD) is an ideal target for early therapeutic intervention because SCD occurs at preclinical stages many years before the onset of Alzheimer's disease (AD). According to a novel lifespan-based model of dementia risk, hearing loss is considered the greatest potentially modifiable risk factor of dementia among nine health and lifestyle factors, and hearing impairment is associated with cognitive decline. Therefore, we propose a neurofeedback training based on MMN, which is an objective index of auditory discriminability, to regulate sensory ability and memory as a non-pharmacological intervention (NPI) in SCD patients. Seventeen subjects meeting the standardized clinical evaluations for SCD received neurofeedback training. The auditory frequency discrimination test, the visual digital N-back (1-, 2-, and 3-back), auditory digital N-back (1-, 2-, and 3-back), and auditory tone N-back (1-, 2-, and 3-back) tasks were used pre- and post-training in all SCD patients. The intervention schedule comprised five 60-min training sessions over 2 weeks. The results indicate that the subjects who received neurofeedback training had successfully improved the amplitude of MMN at the parietal electrode (Pz). A slight decrease in the threshold of auditory frequency discrimination was observed after neurofeedback training. Notably, after neurofeedback training, the working memory (WM) performance was significantly enhanced in the auditory tone 3-back test. Moreover, improvements in the accuracy of all WM tests relative to the baseline were observed, although the changes were not significant. To the best of our knowledge, our preliminary study is the first to investigate the effects of MMN neurofeedback training on WM in SCD patients, and our results suggest that MMN neurofeedback may represent an effective treatment for intervention in SCD patients and the elderly with aging memory decline.
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Cancer stem cell (CSC) is a challenge in the therapy of triple-negative breast cancer (TNBC). Intratumoral hypoxia is a common feature of solid tumor. Hypoxia may contribute to the maintenance of CSC, resulting in a poor efficacy of traditional treatment and recurrence of TNBC cases. However, the underlying molecular mechanism involved in hypoxia-induced CSC stemness maintenance remains unclear. Here, we report that hypoxia stimulated DNA double-strand breaks independent of ATM kinase activation (called oxidized ATM in this paper) play a crucial role in TNBC mammosphere formation and stemness maintenance by governing a specific energy metabolism reprogramming (EMR). Oxidized ATM up-regulates GLUT1, PKM2, and PDHa expressions to enhance the uptake of glucose and production of pyruvate rather than lactate products, which facilitates glycolytic flux to mitochondrial pyruvate and citrate, thus resulting in accumulation of cytoplasmic acetyl-CoA instead of the tricarboxylic acid (TCA) cycle by regulating ATP-citrate lyase (ACLY) activity. Our findings unravel a novel model of TNBC-CSC glucose metabolism and its functional role in maintenance of hypoxic TNBC-CSC stemness. This work may help us to develop new therapeutic strategies for TNBC treatment.
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Acetilcoenzima A/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Metabolismo Energético , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Acetilação , Animais , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Humanos , Camundongos Nus , Modelos Biológicos , Oxirredução , Neoplasias de Mama Triplo Negativas/genética , Hipóxia Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Among the four prostaglandin E2 receptors, EP3 receptor is the one most abundantly expressed in white adipose tissue (WAT). The mouse EP3 gene gives rise to three isoforms, namely EP3α, EP3ß, and EP3γ, which differ only at their C-terminal tails. To date, functions of EP3 receptor and its isoforms in WAT remain incompletely characterized. In this study, we found that the expression of all EP3 isoforms were downregulated in WAT of both db/db and high-fat diet-induced obese mice. Genetic ablation of three EP3 receptor isoforms (EP3-/- mice) or EP3α and EP3γ isoforms with EP3ß intact (EP3ß mice) led to an obese phenotype with increased food intake, decreased motor activity, reduced insulin sensitivity, and elevated serum triglycerides. Since the differentiation of preadipocytes and mouse embryonic fibroblasts to adipocytes was markedly facilitated by either pharmacological blockade or genetic deletion/inhibition of EP3 receptor via the cAMP/PKA/PPARγ pathway, increased adipogenesis may contribute to obesity in EP3-/- and EP3ß mice. Moreover, both EP3-/- and EP3ß mice had increased lipolysis in WAT mainly due to the activated cAMP/PKA/hormone-sensitive lipase pathway. Taken together, our findings suggest that EP3 receptor and its α and γ isoforms are involved in both adipogenesis and lipolysis and influence food intake, serum lipid levels, and insulin sensitivity.