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Cholesterol metabolism is vital for multiple cancer progression, while how cholesterol affects lung, a low-cholesterol tissue, for cancer metastasis and the underlying mechanism remain unclear. In this study, we found that metastatic lung adenocarcinoma cells acquire cellular dehydrocholesterol and cholesterol by endogenous cholesterol biosynthesis, instead of uptake upon cholesterol treatment. Besides, we demonstrated that exogenous cholesterol functions as signaling molecule to induce FOXA3, a key transcription factor for lipid metabolism via GLI2. Subsequently, ChIP-seq analysis and molecular studies revealed that FOXA3 transcriptionally activated Hmgcs1, an essential enzyme of cholesterol biosynthesis, to induce endogenous dehydrocholesterol and cholesterol level for membrane composition change and cell migration. Conversely, FOXA3 knockdown or knockout blocked cholesterol biosynthesis and lung adenocarcinoma metastasis in mice. In addition, the potent FOXA3 inhibitor magnolol suppressed metastatic gene programs in lung adenocarcinoma patient-derived organoids (PDOs). Altogether, our findings shed light onto unique cholesterol metabolism and FOXA3 contribution to lung adenocarcinoma metastasis.
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Adenocarcinoma de Pulmão , Colesterol , Progressão da Doença , Fator 3-gama Nuclear de Hepatócito , Neoplasias Pulmonares , Colesterol/metabolismo , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/genética , Animais , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Camundongos , Fator 3-gama Nuclear de Hepatócito/metabolismo , Fator 3-gama Nuclear de Hepatócito/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Movimento CelularRESUMO
Wavefront coding (WFC) techniques, including optical coding and digital image processing stages, enable significant capabilities for extending the depth of field of imaging systems. In this study, we demonstrated a deeply learned far-infrared WFC camera with an extended depth of field. We designed and optimized a high-order polynomial phase mask by a genetic algorithm, exhibiting a higher defocus consistency of the modulated transfer functions than works published previously. Additionally, we trained a generative adversarial network based on a synthesized WFC dataset for the digital processing part, which is more effective and robust than conventional decoding methods. Furthermore, we captured real-world infrared images using the WFC camera with far, middle, and near object distances. Their results after wavefront coding/decoding showed that the model of deeply learned networks improves the image quality and signal-to-noise ratio significantly and quickly. Therefore, we construct a novel artificial intelligent method of deeply learned WFC optical imaging by applying infrared wavelengths, but not limited to, and provide good potential for its practical application in "smart" imaging and large range target detection.
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Activity of transcriptional co-activator with PDZ binding domain (TAZ) protein is strongly implicated in the pathogenesis of human cancer and is influenced by tumor metabolism. High levels of lactate concentration in the tumor microenvironment as a result of metabolic reprogramming are inversely correlated with patient overall survival. Herein, we investigated the role of lactate in the regulation of the activity of TAZ and showed that glycolysis-derived lactate efficiently increased TAZ expression and activity in lung cancer cells. We showed that the reactive oxygen species (ROS) generated by lactate-fueled oxidative phosphorylation (OXPHOS) in mitochondria activated AKT and thereby inhibited glycogen synthase kinase 3 beta/beta-transducin repeat-containing proteins (GSK-3ß/ß-TrCP)-mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1). Upregulation of DNMT1 by lactate caused hypermethylation of TAZ negative regulator of the LATS2 gene promoter, leading to TAZ activation. Moreover, TAZ binds to the promoter of DNMT1 and is necessary for DNMT1 transcription. Our study showed a molecular mechanism of DNMT1 in linking tumor metabolic reprogramming to the Hippo-TAZ pathway and functional significance of the DNMT1-TAZ feedback loop in the migratory and invasive potential of lung cancer cells.
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DNA (Citosina-5-)-Metiltransferase 1/genética , Ácido Láctico/metabolismo , Estresse Oxidativo/genética , Transativadores/genética , Transcrição Gênica/genética , Ativação Transcricional/genética , Linhagem Celular Tumoral , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , Espécies Reativas de Oxigênio/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador TranscricionalRESUMO
BACKGROUND: Metabolic reprogramming contributes significantly to tumor development and is tightly linked to drug resistance. The chemotherapeutic agent etoposide (VP-16) has been used clinically in the treatment of lung cancer but possess different sensitivity and efficacy towards SCLC and NSCLC. Here, we assessed the impact of etoposide on glycolytic metabolism in SCLC and NSCLC cell lines and investigated the role of metabolic rewiring in mediating etoposide resistance. METHODS: glycolytic differences of drug-treated cancer cells were determined by extracellular acidification rate (ECAR), glucose consumption, lactate production and western blot. DNA damage was evaluated by the comet assay and western blot. Chemoresistant cancer cells were analyzed by viability, apoptosis and western blot. Chromatin immunoprecipitation (ChIP) was used for analysis of DNA-protein interaction. RESULTS: Here we showed that exposure to chemotherapeutic drug etoposide induces an exacerbation of ROS production which activates HIF-1α-mediated the metabolic reprogramming toward increased glycolysis and lactate production in non-small cell lung cancer (NSCLC). We identified lactic acidosis as the key that confers multidrug resistance through upregulation of multidrug resistance-associated protein 1 (MRP1, encoded by ABCC1), a member of ATP-binding cassette (ABC) transporter family. Mechanistically, lactic acid coordinates TGF-ß1/Snail and TAZ/AP-1 pathway to induce formation of Snail/TAZ/AP-1 complex at the MRP1/ABCC1 promoter. Induction of MRP1 expression inhibits genotoxic and apoptotic effects of chemotherapeutic drugs by increasing drug efflux. Furthermore, titration of lactic acid with NaHCO3 was sufficient to overcome resistance. CONCLUSIONS: The chemotherapeutic drug etoposide induces the shift toward aerobic glycolysis in the NSCLC rather than SCLC cell lines. The increased lactic acid in extracellular environment plays important role in etoposide resistance through upregulation of MRP expression. These data provide first evidence for the increased lactate production, upon drug treatment, contributes to adaptive resistance in NSCLC and reveal potential vulnerabilities of lactate metabolism and/or pathway suitable for therapeutic targeting. Video Abstract The chemotherapeutic drug etoposide induces metabolic reprogramming towards glycolysis in the NSCLC cells. The secreted lactic acid coordinates TGF-ß1/Snail and TAZ/AP-1 pathway to activate the expression of MRP1/ABCC1 protein, thus contributing to chemoresistance in NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Etoposídeo/farmacologia , Lactatos/farmacologia , Neoplasias Pulmonares/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lactatos/metabolismo , Mutagênicos/toxicidade , Fatores de Transcrição da Família Snail/metabolismo , Fator de Transcrição AP-1/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Regulação para Cima/efeitos dos fármacosRESUMO
Filial piety in traditional Chinese culture is an essential variable in explaining intergenerational interaction. However, previous studies have not clarified whether older adults' filial responsibility expectations matched children's filial support and the effects of the filial discrepancy on their life satisfaction and loneliness. The latent profile analysis showed that older adults were divided into two groups: (1) high expectations and support, and (2) low expectations and support. The results showed that compared with older adults with low expectations and low support, those with high expectations and high support reported higher life satisfaction and lower loneliness. Additionally, social support played a moderating role in the effect of the groups of older adults on life satisfaction and loneliness. Our conclusion shows that filial support is an essential factor influencing older adult life satisfaction and loneliness, and social support is an effective supplement to filial support.
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BACKGROUND AND AIM: Triglyceride (TG) levels are closely related to obesity, fatty liver and cardiovascular diseases, while the regulatory factors and mechanism for triglyceride homeostasis are still largely unknown. Zinc Finger Protein 638 (ZNF638) is a newly discovered member of zinc finger protein family for adipocyte function in vitro. The aim of the present work was to investigate the role of ZNF638 in regulating triglyceride metabolism in mice. METHODS: We generated ZNF638 adipose tissue specific knockout mice (ZNF638 FKO) by cross-breeding ZNF638 flox to Adiponectin-Cre mice and achieved adipose tissue ZNF638 overexpression via adenoviral mediated ZNF638 delivery in inguinal adipose tissue (iWAT) to examined the role and mechanisms of ZNF638 in fat biology and whole-body TG homeostasis. RESULTS: Although ZNF638 FKO mice showed similar body weights, body composition, glucose metabolism and serum parameters compared to wild-type mice under chow diet, serum TG levels in ZNF638 FKO mice were increased dramatically after refeeding compared to wild-type mice, accompanied with decreased endothelial lipoprotein lipase (LPL) activity and increased lipid absorption of the small intestine. Conversely, ZNF638 overexpression in iWAT reduced serum TG levels while enhanced LPL activity after refeeding in female C57BL/6J mice and obese ob/ob mice. Specifically, only female mice exhibited altered TG metabolism upon ZNF638 expression changes in fat. Mechanistically, RNA-sequencing analysis revealed that the TG regulator angiopoietin-like protein 8 (Angptl8) was highly expressed in iWAT of female ZNF638 FKO mice. Neutralizing circulating ANGPTL8 in female ZNF638 FKO mice abolished refeeding-induced TG elevation. Furthermore, we demonstrated that ZNF638 functions as a transcriptional repressor by recruiting HDAC1 for histone deacetylation and broad lipid metabolic gene suppression, including Angptl8 transcription inhibition. Moreover, we showed that the sexual dimorphism is possibly due to estrogen dependent regulation on ZNF638-ANGPTL8 axis. CONCLUSION: We revealed a role of ZNF638 in the regulation of triglyceride metabolism by affecting Angptl8 transcriptional level in adipose tissue with sexual dimorphism.
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Tecido Adiposo , Proteína 8 Semelhante a Angiopoietina , Proteínas de Ligação a DNA , Proteínas de Ligação a RNA , Triglicerídeos , Animais , Feminino , Camundongos , Tecido Adiposo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Metabolismo dos Lipídeos/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo , Triglicerídeos/metabolismo , Dedos de ZincoRESUMO
The de novo differentiation of hyperplastic adipocytes from adipocyte progenitor cells (APCs) is accompanied by a reduction in adipose tissue fibrosis and inflammation and improvement in insulin sensitivity in obesity and aging. However, the regulators of APC proliferation are poorly understood. Here, we show that fibroblast growth factor 6 (FGF6) acts in an autocrine and/or paracrine manner to control platelet-derived growth factor receptor α-positive APC proliferation via extracellular signal-regulated kinase (ERK) signaling. Specific FGF6 overexpression in inguinal white adipose tissue (iWAT) improved the signs of high-fat diet- or aging-induced adipose hypertrophy and insulin resistance. Conversely, chronic FGF6 expression blockade in iWAT, mediated by a neutralizing antibody or Fgf6 expression deficiency, impaired adipose tissue expansion and glucose tolerance. Overall, our data suggest that FGF6 acts as a proliferative factor for APCs to maintain fat homeostasis and insulin sensitivity.
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Resistência à Insulina , Neoplasias , Animais , Camundongos , Fator 6 de Crescimento de Fibroblastos/metabolismo , Tecido Adiposo/metabolismo , Adipócitos/metabolismo , Tecido Adiposo Branco/metabolismo , Obesidade/metabolismo , Neoplasias/metabolismo , Proliferação de Células , Homeostase , Dieta Hiperlipídica , Camundongos Endogâmicos C57BLRESUMO
Metastasis is a leading cause of mortality in patients with lung adenocarcinoma. Histone deacetylases have emerged as promising targets for anti-tumor drugs, with histone deacetylase inhibitors (HDACi) being an active area of research. However, the precise mechanisms by which HDACi inhibits lung cancer metastasis remain incompletely understood. In this study, we employed a range of techniques, including qPCR, immunoblotting, co-immunoprecipitation, chromatin-immunoprecipitation, and cell migration assays, in conjunction with online database analysis, to investigate the role of HDACi and HDAC2/YY1 in the process of lung adenocarcinoma migration. The present study has demonstrated that both trichostatin A (TSA) and sodium butyrate (NaBu) significantly inhibit the invasion and migration of lung cancer cells via Histone deacetylase 2 (HDAC2). Overexpression of HDAC2 promotes lung cancer cell migration, whereas shHDAC2 effectively inhibits it. Further investigation revealed that HDAC2 interacts with YY1 and deacetylates Lysine 27 and Lysine9 of Histone 3, thereby inhibiting Cdh1 transcriptional activity and promoting cell migration. These findings have shed light on a novel functional mechanism of HDAC2/YY1 in lung adenocarcinoma cell migration.
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Adenocarcinoma de Pulmão , Antígenos CD , Caderinas , Histona Desacetilase 2 , Inibidores de Histona Desacetilases , Metástase Neoplásica , Fator de Transcrição YY1 , Humanos , Animais , Camundongos , Feminino , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/enzimologia , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Movimento Celular/efeitos dos fármacos , Ácido Butírico/farmacologia , Ácido Butírico/uso terapêutico , Fator de Crescimento Transformador beta/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Histona Desacetilase 2/antagonistas & inibidores , Histona Desacetilase 2/metabolismo , Fator de Transcrição YY1/metabolismo , Caderinas/genética , Caderinas/metabolismo , Antígenos CD/metabolismo , Ligação Proteica , Transcrição Gênica , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/patologia , Metástase Neoplásica/prevenção & controleRESUMO
Macrophages have critical contributions to both acute and chronic inflammatory diseases, for example, bowel disease and obesity, respectively. However, little is known about the post-transcriptional regulatory mechanisms in macrophage-mediated inflammatory diseases. hnRNPA2B1 (A2B1) is an RNA binding protein for mRNA fate determination. We showed that hnRNPA2B1 mRNA levels were increased in colon in dextran sodium sulfate (DSS)-induced colitis mice and in epididymal white adipose tissue (eWAT) and spleen of high-fat-diet (HFD)-induced obese mice. Consistently, mice with haploinsufficiency of A2B1 (A2B1 HET) are protected against DSS-induced acute colitis and HFD-induced obesity, with decreased M1 macrophages polarization in colon, eWAT and spleen. Mechanistically, A2B1 mRNA and protein levels were increased in LPS-stimulated RAW 264.7 macrophages, and A2B1 enhanced RNA stability of pro-inflammatory genes Tnfα, Il-6 and Il-1ß for the regulation of macrophages polarization. Interestingly, A2B1 HET mice exhibited reduced white fat expansion, which was influenced by macrophages, since conditioned medium from macrophages with A2B1 manipulation significantly changed preadipocyte proliferation. Our data demonstrate that A2B1 plays a vital role in macrophage-mediated inflammation via regulating mRNA stability, suggesting that A2B1 may be served as a promising target for the intervention of acute and chronic inflammatory diseases.
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Colite , Inflamação , Camundongos , Animais , Camundongos Endogâmicos C57BL , Inflamação/metabolismo , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Macrófagos/metabolismo , Obesidade/genética , Obesidade/metabolismo , Camundongos Obesos , Sulfato de Dextrana/efeitos adversosRESUMO
Background & Aims: Liver regeneration is vital for the recovery of liver function after injury, yet the underlying mechanism remains to be elucidated. Forkhead box protein A3 (FOXA3), a member of the forkhead box family, plays important roles in endoplasmic reticulum stress sensing, and lipid and glucose homoeostasis, yet its functions in liver regeneration are unknown. Methods: Here, we explored whether Foxa3 regulates liver regeneration via acute and chronic liver injury mice models. We further characterised the molecular mechanism by chromatin immunoprecipitation sequencing and rescue experiments in vivo and in vitro. Then, we assessed the impact of Foxa3 pharmacological activation on progression and termination of liver regeneration. Finally, we confirmed the Foxa3-Cebpb axis in human liver samples. Results: Foxa3 is dominantly expressed in hepatocytes and cholangiocytes and is induced upon partial hepatectomy (PH) or carbon tetrachloride (CCl4) administration. Foxa3 deficiency in mice decreased cyclin gene levels and delayed liver regeneration after PH, or acute or chronic i.p. CCl4 injection. Conversely, hepatocyte-specific Foxa3 overexpression accelerated hepatocytes proliferation and attenuated liver damage in an CCl4-induced acute model. Mechanistically, Foxa3 directly regulates Cebpb transcription, which is involved in hepatocyte division and apoptosis both in vivo and in vitro. Of note, Cebpb overexpression in livers of Foxa3-deficient mice rescued their defects in cell proliferation and regeneration upon CCl4 treatment. In addition, pharmacological induction of Foxa3 via cardamonin speeded up hepatocyte proliferation after PH, without interfering with liver regeneration termination. Finally, Cebpb and Ki67 levels had a positive correlation with Foxa3 expression in human chronic disease livers. Conclusions: These data characterise Foxa3 as a vital regulator of liver regeneration, which may represent an essential factor to maintain liver mass after liver injury by governing Cebpb transcription. Impact and Implications: Liver regeneration is vital for the recovery of liver function after chemical insults or hepatectomy, yet the underlying mechanism remains to be elucidated. Herein, via in vitro and in vivo models and analysis, we demonstrated that Forkhead box protein A3 (FOXA3), a Forkhead box family member, maintained normal liver regeneration progression by governing Cebpb transcription and proposed cardamonin as a lead compound to induce Foxa3 and accelerate liver repair, which signified that FOXA3 may be a potential therapeutic target for further preclinical study on treating liver injury.
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PURPOSE: The epithelial-to-mesenchymal transition (EMT) is a fundamental process in tumor progression that endows cancer cells with migratory and invasive potential. Snail, a zinc finger transcriptional repressor, plays an important role in the induction of EMT by directly repressing the key epithelial marker E-cadherin. Here, we assessed the effect of urolithin A, a major metabolite from pomegranate ellagitannins, on Snail expression and EMT process. METHODS: The role of Snail in urolithin A-induced EMT inhibition in lung cancer cells was explored by wound healing assay and cell invasion assay. The qRT-PCR and CHX assay were performed to investigate how urolithin A regulates Snail expression. Immunoprecipitation assays were established to determine the effects of urolithin A in mdm2-Snail interaction. In addition, the expression of p53 was manipulated to explore its effect on the expression of mdm2 and Snail. RESULTS: The urolithin A dose-dependently upregulated epithelial marker and decreased mesenchymal markers in lung cancer cells. In addition, exposure to urolithin A decreased cell migratory and invasive capacity. We have further demonstrated that urolithin A inhibits lung cancer cell EMT by decreasing Snail protein expression and activity. Mechanistically, urolithin A disrupts the interaction of p53 and mdm2 which leads Snail ubiquitination and degradation. CONCLUSION: We conclude that urolithin A could inhibit EMT process by controlling mainly Snail expression. These results highlighted the role of pomegranate in regulation of EMT program in lung cancer.
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Highly expressed G protein-coupled receptor 81 (GPR81), a receptor for lactate, is emerging as a critical regulator of tumor growth and metastasis. However, the mechanistic basis for its highly expression in cancer cells remains elusive. Here we report that tumor-derived lactate transcriptionally regulates GPR81 expression. We demonstrated that the transcriptional response of GPR81 to lactate is mediated by Signal transducer and activator of transcription 3 (STAT3). Mechanistically, lactate upregulates transcriptional factor Snail and induces the assembly of Snail/EZH2/STAT3 complex. Within this ternary complex, STAT3 activity is strongly enhanced. Consequently, the activated STAT3 by lactate directly binds GPR81promoter and activates its expression. These findings shed light on the transcriptional mechanism by which GPR81 expression is regulated in cancer cells, and provides mechanistic insight into how aberrant signaling and continually high lactate levels due to metabolic switch may yield a feed-forward/self-enabling loop to promote tumor progression.
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Ácido Láctico/farmacologia , Neoplasias Pulmonares/genética , Receptores Acoplados a Proteínas G/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Fatores de Transcrição da Família Snail/genética , Células A549 , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Neoplasias Pulmonares/patologia , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/genética , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
To examine Ca2+ absorption and transportation in the freshwater pearl oyster, Hyriopsis cumingii Lea, we studied the effects of different levels of either extracellular Ca2+ or 1,25(OH)2D3 on extracellular Ca2+ flux and intracellular Ca2+ concentrations in mantle cells using the non-invasive micro-test technique and laser scanning confocal microscopy. The inner and outer mantle (IM and OM) cells from mussels were cultured and then treated with different concentrations of Ca2+ and 1,25(OH)2D3. Extracellular Ca2+ flux and intracellular Ca2+ reserves were analyzed. The results showed that both extracellular Ca2+ and 1,25(OH)2D3 had significant effects on Ca2+ flux and reserves in mantle cells, especially in IM cells (Pâ¯<â¯.05). The increase in extracellular Ca2+ concentrations resulted in the conversion of extracellular Ca2+ flux into influx with an increase in flow rate (Pâ¯<â¯.05). The calcium ion fluorescence intensity of OM cells was higher than that of IM cells (Pâ¯<â¯.05). 1,25(OH)2D3 addition also significantly increased the influx rate of extracellular Ca2+, especially in IM cells, which were more sensitive to 1,25(OH)2D3 addition and had significantly higher Ca2+ influx rates than did OM cells (Pâ¯<â¯.05). Fluorescence intensities of intracellular Ca2+ first increased and then decreased with increasing 1,25(OH)2D3 levels. The study showed that IM cells play an important role in absorbing Ca2+ from the environment, while OM cells mainly function in the temporary storage and transportation of Ca2+ in the body. The current results suggested that high levels of extracellular Ca2+ (1.25â¯mM) or 1,25(OH)2D3 (over 100â¯IU/L) were favorable for Ca2+ uptake and maintenance in the body.
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Absorção Fisiológica , Exoesqueleto/metabolismo , Calcitriol/metabolismo , Sinalização do Cálcio , Cálcio/metabolismo , Pinctada/fisiologia , Exoesqueleto/citologia , Animais , Aquicultura , Transporte Biológico , Células Cultivadas , China , Corantes Fluorescentes/química , Eletrodos Seletivos de Íons , Cinética , Microscopia Confocal , Pinctada/crescimento & desenvolvimento , Reprodutibilidade dos TestesRESUMO
BACKGROUND: The preferential use of aerobic glycolysis by tumor cells lead to high accumulation of lactate in tumor microenvironment. Clinical evidence has linked elevated lactate concentration with cancer outcomes. However, the role and molecular mechanisms of lactate in cellular senescence and tumor progression remain elusive. METHODS: The function of Snail in lactate-induced EMT in lung cancer cells was explored by wound healing assay and cell invasion assay. The qRT-PCR and dual luciferase reporter assay were performed to investigate how lactate regulates Snail expression. The level of TGF-ß1 in culture supernatant of cells was measured by ELISA for its correlation with extracellular levels of lactate. Ras activity assay and SA-ß-gal activity assay were established to determine the effect of lactate on oncogene-induced senescence in human lung epithelial cells. ChIP assays were conducted to determine the binding of snail to p16INK4a promoter. Two TCGA data sets (TCGA-LUAD and TCGA-LUSC) were used to explore the correlations between SNAI1 and CDKN2A expression. RESULTS: In this study, we showed the invasive and migratory potential of lung cancer cells was significantly enhanced by lactate and was directly linked to snail activity. We also demonstrated that extracellular acidification itself is a direct cause of the increased snail expression and physiologically coupled to LDHA-dependent conversion of pyruvate to lactate. Mechanistically, lactate exerts its central function in induction of snail and EMT by directly remodeling ECM and releasing activated TGF-ß1. We also demonstrated that Snail help premalignant cells to escape the oncogene-induced senescence by directly targeting and inhibiting p16INK4a expression. CONCLUSIONS: Our study extends the understanding of EMT in tumorigenesis by uncovering the role of snail in cellular senescence. This study also reveals lactate may be a potent tumor-promoting factor and provides the basis for the development of lactate-targeted therapy.