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Pancreatic neuroendocrine neoplasms (PanNENs) are a group of highly heterogeneous neoplasms originating from the endocrine islet cells of the pancreas with characteristic neuroendocrine differentiation, more than 60% of which represent metastases when diagnosis, causing major tumor-related death. Metabolic alterations have been recognized as one of the hallmarks of tumor metastasis, providing attractive therapeutic targets. However, little is known about the molecular mechanism of metabolic changes regulating PanNEN progression. In this study, we first identified methylmalonic acid (MMA) as an oncometabolite for PanNEN progression, based on serum metabolomics of metastatic PanNEN compared with non-metastatic PanNEN patients. One of the key findings was the potentially novel mechanism of epithelial-mesenchymal transition (EMT) triggered by MMA. Inhibin ßA (INHBA) was characterized as a key regulator of MMA-induced PanNEN progression according to transcriptomic analysis, which has been validated in vitro and in vivo. Mechanistically, INHBA was activated by FOXA2, a neuroendocrine (NE) specific transcription factor, which was initiated during MMA-induced progression. In addition, MMA-induced INHBA upregulation activated downstream MITF to regulate EMT-related genes in PanNEN cells. Collectively, these data suggest that activation of INHBA via FOXA2 promotes MITF-mediated EMT during MMA inducing PanNEN progression, which puts forward a novel therapeutic target for PanNENs.
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Factor Nuclear 3-beta del Hepatocito , Subunidades beta de Inhibinas , Ácido Metilmalónico , Neoplasias Pancreáticas , Humanos , Factor Nuclear 3-beta del Hepatocito/genética , Subunidades beta de Inhibinas/genética , Páncreas , Neoplasias Pancreáticas/genética , Activación TranscripcionalRESUMEN
BACKGROUND: Pancreatic neuroendocrine neoplasms (pNENs) are relatively rare. Hypoxia and lipid metabolism-related gene acetyl-CoA synthetase 2 (ACSS2) is involved in tumor progression, but its role in pNENs is not revealed. This study showed that hypoxia can upregulate ACSS2, which plays an important role in the occurrence and development of pNENs through lipid metabolism reprogramming. However, the precise role and mechanisms of ACSS2 in pNENs remain unknown. METHODS: mRNA and protein levels of ACSS2 and 3-hydroxy-3-methylglutaryl-CoA synthase1 (HMGCS1) were detected using quantitative real-time PCR (qRT-PCR) and Western blotting (WB). The effects of ACSS2 and HMGCS1 on cell proliferation were examined using CCK-8, colony formation assay and EdU assay, and their effects on cell migration and invasion were examined using transwell assay. The interaction between ACSS2 and HMGCS1 was verified by Co-immunoprecipitation (Co-IP) experiments, and the functions of ACSS2 and HMGCS1 in vivo were determined by nude mouse xenografts. RESULTS: We demonstrated that hypoxia can upregulate ACSS2 while hypoxia also promoted the progression of pNENs. ACSS2 was significantly upregulated in pNENs, and overexpression of ACSS2 promoted the progression of pNENs and knockdown of ACSS2 and ACSS2 inhibitor (ACSS2i) treatment inhibited the progression of pNENs. ACSS2 regulated lipid reprogramming and the PI3K/AKT/mTOR pathway in pNENs, and ACSS2 regulated lipid metabolism reprogramming through the PI3K/AKT/mTOR pathway. Co-IP experiments indicated that HMGCS1 interacted with ACSS2 in pNENs. Overexpression of HMGCS1 can reverse the enhanced lipid metabolism reprogramming and tumor-promoting effects of knockdown of ACSS2. Moreover, overexpression of HMGCS1 reversed the inhibitory effect of knockdown of ACSS2 on the PI3K/AKT/mTOR pathway. CONCLUSION: Our study revealed that hypoxia can upregulate the lipid metabolism-related gene ACSS2, which plays a tumorigenic effect by regulating lipid metabolism through activating the PI3K/AKT/mTOR pathway. In addition, HMGCS1 can reverse the oncogenic effects of ACSS2, providing a new option for therapeutic strategy.
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Metabolismo de los Lípidos , Neoplasias Pancreáticas , Humanos , Animales , Ratones , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Reprogramación Metabólica , Serina-Treonina Quinasas TOR , Lípidos , Acetato CoA Ligasa , Hidroximetilglutaril-CoA SintasaRESUMEN
BACKGROUND: This study reported the safety and efficacy of a phase 2, open-label, single-arm, exploratory clinical trial of induction immunochemotherapy in patients with initially unresectable advanced esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Patients underwent three cycles of induction therapy with tislelizumab, cisplatin, and 5-fluorouracil. The primary endpoints were the safety, major pathological response (MPR), and pathological complete response (pCR). Secondary endpoints included the R0 resection rate, disease-free survival (DFS), and overall survival (OS). Genomic data and immune microenvironment data were analyzed exploratively. RESULTS: The treatment was safe, with a grade 3 or higher adverse event rate of 14.9% (7/47). Of the total 47 patients enrolled in the study, 19 (40.4%) achieved MPR, 12 (25.5%) achieved pCR, 4 (8.5%) achieved complete clinical response (cCR) and declined surgery, and 23 (48.94%) underwent successful resection. Median follow-up was 18 months, with a median DFS of 24 months, a median OS of 36 months. A high tumor mutation burden was associated with a better prognosis for patients who underwent surgery. Patients who achieved pCR had higher levels of immune cell infiltration and a greater proportion and concentration of tertiary lymphoid structures compared with those who experienced a major pathological response. CONCLUSIONS: Tislelizumab combined with chemotherapy is effective for ESCC, yielding high cCR, pCR, surgical conversion, and R0 resection rates, and tolerable adverse events. TRIAL REGISTRATION: NCT05469061.
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N6-methyladenosine modification, especially Wilms tumor 1-associated protein (WTAP), is reportedly associated with a variety of cancers, including colorectal cancer (CRC). Angiogenesis also plays an important role in the occurrence and development of CRC. However, only a few studies have reported the biological mechanisms underlying this connection. Therefore, tissue microarray and public database were used to explore WTAP levels in CRC. Then, WTAP was down-regulated and over-expressed, respectively. CCK8, EdU, colony formation, and transwell experiments were performed to study the role of WTAP in CRC. Combined RNA sequencing and m6A RNA immunoprecipitation (MeRIP) sequencing, we found downstream molecules VEGFA. Moreover, a tube formation assay was executed for tumor angiogenesis. Finally, a subcutaneous tumorigenesis assay in nude mice was used to examine the tumor-promoting effect of WTAP in vivo. In the present study, WTAP was significantly upregulated in CRC cells and patients with CRC. Moreover, higher WTAP expression was observed in the TCGA and CPATC databases in CRC tissues. WTAP over-expression exacerbates cell proliferation, migration, invasion, and angiogenesis. Conversely, WTAP knockdown inhibited the malignant biological behavior of CRC cells. Mechanistically, WTAP positively regulated VEGFA, as identified using RNA sequencing and MeRIP sequencing. Moreover, we identified YTHDC1 as a downstream effector of the YTHDC1-VEGFA axis in CRC. Furthermore, increased WTAP expression activated the MAPK signaling pathway, which led to enhanced angiogenesis. In conclusion, our study revealed that the WTAP/YTHDC1/VEGFA axis promotes CRC development, especially angiogenesis, suggesting that it may act as a potential biomarker of CRC.
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Adenosina , Neoplasias Colorrectales , Animales , Ratones , Bioensayo , Neoplasias Colorrectales/genética , Metilación , Ratones Desnudos , HumanosRESUMEN
Pancreatic neuroendocrine neoplasms (pNENs) are among the most frequently occurring neuroendocrine neoplasms (NENs) and require targeted therapy. High levels of fatty acid binding protein 5 (FABP5) are involved in tumor progression, but its role in pNENs remains unclear. We investigated the mRNA and protein levels of FABP5 in pNEN tissues and cell lines and found them to be upregulated. We evaluated changes in cell proliferation using CCK-8, colony formation, and 5-ethynyl-2'-deoxyuridine assays and examined the effects on cell migration and invasion using transwell assays. We found that knockdown of FABP5 suppressed the proliferation, migration, and invasion of pNEN cell lines, while overexpression of FABP5 had the opposite effect. Co-immunoprecipitation experiments were performed to clarify the interaction between FABP5 and fatty acid synthase (FASN). We further showed that FABP5 regulates the expression of FASN via the ubiquitin proteasome pathway and both proteins facilitate the progression of pNENs. Our study demonstrated that FABP5 acts as an oncogene by promoting lipid droplet deposition and activating the WNT/ß-catenin signaling pathway. Moreover, the carcinogenic effects of FABP5 can be reversed by orlistat, providing a novel therapeutic intervention option.
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Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Vía de Señalización Wnt , Línea Celular Tumoral , Metabolismo de los Lípidos/genética , beta Catenina/genética , beta Catenina/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Tumores Neuroendocrinos/genética , Ácido Graso Sintasas/genética , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/farmacología , Proliferación Celular/genética , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Unión a Ácidos Grasos/genética , Proteínas de Unión a Ácidos Grasos/metabolismo , Proteínas de Unión a Ácidos Grasos/farmacología , Acido Graso Sintasa Tipo I/genética , Acido Graso Sintasa Tipo I/metabolismoRESUMEN
The process of post-transcriptional regulation has been recognized to be significantly impacted by the presence of N6-methyladenosine (m6A) modification. As an m6A demethylase, ALKBH5 has been shown to contribute to the progression of different cancers by increasing expression of several oncogenes. Hence, a better understanding of the key targets of ALKBH5 in cancer cells could potentially lead to the development of new therapeutic targets. However, the specific role of ALKBH5 in pancreatic neuroendocrine neoplasms (pNENs) remains largely unknown. Here, we demonstrated that ALKBH5 was up-regulated in pNENs and played a critical role in tumor growth and lipid metabolism. Mechanistically, ALKBH5 over-expression was found to increase the expression of FABP5 in an m6A-IGF2BP2 dependent manner, leading to disorders in lipid metabolism. Additionally, ALKBH5 was found to activate PI3K/Akt/mTOR signaling pathway, resulting in enhanced lipid metabolism and proliferation abilities. In conclusion, our study uncovers the ALKBH5/IGF2BP2/FABP5/mTOR axis as a mechanism for aberrant m6A modification in lipid metabolism and highlights a new molecular basis for the development of therapeutic strategies for pNENs treatment.
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Metabolismo de los Lípidos , Neoplasias Pancreáticas , Humanos , Metabolismo de los Lípidos/genética , Fosfatidilinositol 3-Quinasas , Neoplasias Pancreáticas/genética , Adenosina , Serina-Treonina Quinasas TOR , Proteínas de Unión a Ácidos Grasos/genética , Proteínas de Unión al ARN , Desmetilasa de ARN, Homólogo 5 de AlkB/genéticaRESUMEN
BACKGROUND: It has been manifested in several studies that age-related metabolic reprogramming is associated with tumor progression, in particular, colorectal cancer (CRC). Here we investigated the role of upregulated metabolites of the aged serum, including methylmalonic acid (MMA), phosphoenolpyruvate (PEP), and quinolinate (QA), in CRC. METHODS: Functional assays including CCK-8, EdU, colony formation and transwell experiments were used to ascertain which upregulated metabolite of elderly serum was related to tumor progression. RNA-seq analysis was conducted to explore the potential mechanisms of MMA-induced CRC progression. Subcutaneous tumorigenesis and metastatic tumor models were constructed to verify the function of MMA in vivo. RESULTS: Among three consistently increased metabolites of the aged sera, MMA was responsible for tumorigenesis and metastasis in CRC, according to functional assays. The promotion of Epithelial-mesenchymal transition (EMT) was observed in CRC cells treated with MMA, on the basis of protein expression of EMT markers. Moreover, combined with transcriptome sequencing, Wnt/ß-catenin signaling pathway was activated in CRC cells treated with MMA, which was verified by western blot and qPCR experiments. Furthermore, animal assays demonstrated the pro-proliferation and promotion of metastasis role of MMA in vivo. CONCLUSION: We have identified that age-dependent upregulation of MMA in serum promoted the progression of CRC via Wnt/ß-catenin signaling pathway mediated EMT. These collective findings provide valuable insights into the vital role of age-related metabolic reprogramming in CRC progression and propose a potential therapeutic target for elderly CRC.
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Objective:To perform a meta-analysis of published randomized controlled trials (RCTs) to assess the effects of curcumin supplementation with different formulations on anthropometric and cardiometabolic indices in patients with metabolism-related diseases (MRDs). Methods: Six databases, including PubMed, Embase, Web of Science, China national knowledge internet (CNKI), Wanfang and China Biology Medicine (CBM), were systematically searched to find relevant articles from 2011 to July 2021. The effect sizes were expressed as weighted mean difference (WMD) with 95% confidence intervals (CI). Between-study heterogeneity was assessed using I2. Subgroup analysis was conducted to find possible sources of heterogeneity. Curcumin formulations in this study were divided as low bioavailability, high bioavailability and nanocurcumin. Results: Of the retrieved 1585 articles, 31 were included in the final analysis. Combined effect sizes suggested a significant effect of curcumin supplementation on reduced body weight (BW) (WMD: -0.94 kg, 95% CI: -1.40, -0.47) and body mass index (BMI) (WMD: -0.40 kg/m2, 95% CI: -0.60, -0.19), respectively. The results also showed significant improvements of fasting plasma glucose (FPG) (WMD: -0.50 mg/dL, 95% CI: -0.72, -0.28), glycosylated hemoglobin (Hb1Ac) (WMD: -0.42%, 95% CI: -0.57, -0.26), insulin (INS) (WMD: -1.70 µIU/mL, 95%CI: -2.03, -1.38), homeostasis model assessment-insulin resistance (HOMA-IR) (WMD: -0.71, 95%CI: -1.11, -0.31), high-density lipoprotein cholesterol (HDL-C) (WMD: 1.73 mg/dL, 95%CI: 0.78, 2.68) and high sensitivity C-reactive protein (Hs-CRP) (WMD: -1.11, 95%CI: -2.16, -0.05). Nanocurcumin showed a greater reduction in FPG (WMD: -1.78 mg/dL, 95% CI: -2.49, -1.07), INS (WMD: -1.66 µIU/mL, 95% CI: -3.21, -0.11), TC (WMD: -12.64 mg/dL (95% CI: -23.72, -1.57) and LDL-C (WMD: -8.95 mg/dL, 95% CI: -16.51, -1.38). The dose-effect analysis showed that there were trends of first rising and then falling between the supplemented curcumin dose and BW, BMI, LDL-C, Hb1Ac, which were clearly distinguished at 80 mg/d due to the strong effect of nanocurcumin on outcomes. A slow upward trend between the dose of curcumin supplementation and HDL-C. No relationships between dose and outcomes were found for FPG and insulin, except for nanocurcumin at 80 mg/d. Conclusions: Our study showed some significant beneficial effects of curcumin supplementation on improving BW, BMI, and the levels of FPG, Hb1Ac, HOMA-IR, HDL-C and Hs-CRP in patients with MRDs. Nanocurcumin may have a greater effect on the reduction of FPG, INS, TC and LDL-C than other curcumin formulations. Considering the potential bias and limitations of studies included, further quality studies with larger sample sizes are needed to confirm these results.
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Enfermedades Cardiovasculares , Curcumina , Resistencia a la Insulina , Humanos , Proteína C-Reactiva/análisis , Curcumina/farmacología , LDL-Colesterol , Ensayos Clínicos Controlados Aleatorios como Asunto , Peso Corporal , Suplementos Dietéticos/análisis , HDL-Colesterol , Insulina , Enfermedades Cardiovasculares/prevención & control , GlucemiaRESUMEN
A metal-free and efficient approach for the synthesis of structurally important nicotinates through 4-HO-TEMPO-mediated [3 + 3] annulation of cyclopropanols with ß-enamine esters is presented. This protocol features high atom efficiency, green waste, simple operation and broad substrate scope. Moreover, the experiments of gram-scale synthesis and recovery of oxidants make this strategy more sustainable and practical.
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To evaluate the efficacy and safety of intra-tunnel dissection using hemostatic forceps and needle-type device for patients with esophageal circumferential lesions (ECLs). Patients with ECLs were enrolled in the study and underwent endoscopic submucosal tunnel dissection (ESTD) or hemostatic forceps-based ESTD (ESFTD). All patients were divided into three subgroups according to longitudinal length of the lesions (LLLs): >8 cm, 4-8 cm and < 4 cm. The clinical data such as gender, age, length of lesions and operating time were collected. A total of 152 patients were included in this study and comprised 80 cases of ESFTD and 72 cases of ESTD. The procedure time was markedly shorter in the ESFTD group than in the ESTD group (P < 0.001). Moreover, ESFTD significantly increased the rate of complete resection and reduced specimen injury in LLLs >8 cm and 4-8 cm subgroup compared with ESTD (P < 0.001), but not in <4 cm subgroup (P > 0.05). The perforation and infection rate were similar in ESFTD and ESTD group (P > 0.05). However, ESFTD effectively decreased the muscular injury rate' the duration of chest pain and the time from endoscopic surgery to first occurrence of esophageal stenosis compared with ESTD group (P < 0.01). ESFTD has better efficacy and safety than ESTD in the treatment of ECLs, especially for large lesions. ESFTD could be recommended for patients with ECLs.
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Resección Endoscópica de la Mucosa , Neoplasias Esofágicas , Estenosis Esofágica , Hemostáticos , Humanos , Neoplasias Esofágicas/cirugía , Endoscopía , Estenosis Esofágica/etiología , Estenosis Esofágica/epidemiología , Resección Endoscópica de la Mucosa/efectos adversos , Resección Endoscópica de la Mucosa/métodos , Márgenes de Escisión , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Background: The incidence of poorly differentiated gastric neuroendocrine neoplasms (G-NENs) has been increasing during the past decades. Methods: A total of 183 patients diagnosed with poorly differentiated G-NENs were enrolled from eight hospitals during 2010-2019 in China. All cases included have accepted abdominal surgery in tertiary hospitals. Result: T3 (HR: 2.66, p = 0.019), T4 (HR: 3.62, p = 0.005), stage IV (HR: 5.67, p < 0.001), vascular invasion (HR: 1.59, p = 0.048) were independent risk factors for poor prognosis of poorly differentiated G-NENs. In stratified analysis, for patients with stage III tumors, those treated with chemotherapy had significantly longer survival than those accepting surgery alone. Conclusion: T3/T4 stage, TNM stage IV and vascular invasion were independent negative prognostic factors for patients with poorly differentiated G-NENs. Patients with stage III tumors can benefit from chemotherapy. Highly selected patients with stage IV tumors may also benefit from surgery.
This study mainly describes a rare cancerous gastric tumor. Numerous people have been diagnosed with this disease during the past decades. Owing to the small number of patients diagnosed with this disease, the treatment method is still not clear. In our study, we found that the outcome of patients who were diagnosed at late stage was much poorer than those diagnosed at early stage. So, it is important for patients to get accurate diagnosis in time. For a part of patients accepting surgery, they may benefit from chemotherapy.
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Tumores Neuroendocrinos , Neoplasias Gástricas , China/epidemiología , Humanos , Incidencia , Estadificación de Neoplasias , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/epidemiología , Tumores Neuroendocrinos/terapia , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/terapiaRESUMEN
Image stitching refers to stitching two or more images with overlapping areas through feature points matching to generate a panoramic image, which plays an important role in geological survey, military reconnaissance, and other fields. At present, the existing image stitching technologies mostly adopt images with good lighting conditions, but the lack of feature points in scenes with weak light such as morning or night will affect the image stitching effect, making it difficult to meet the needs of practical applications. When there exist concentrated areas of brightness such as lights and large dark areas in the nighttime image, it will further cause the loss of image details making the feature point matching unavailable. The obtained perspective transformation matrix cannot reflect the mapping relationship of the entire image, resulting in poor splicing effect, and it is difficult to meet the actual application requirements. Therefore, an adaptive image enhancement algorithm is proposed based on guided filtering to preprocess the nighttime image, and use the enhanced image for feature registration. The experimental results show that the image obtained by preprocessing the nighttime image with the proposed enhancement algorithm has better detail performance and color restoration, and greatly improves the image quality. By performing feature registration on the enhanced image, the number of matching logarithms of the image increases, so as to achieve high accuracy for images stitching.
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BACKGROUND: To investigate the recent epidemiological trends of gastric neuroendocrine neoplasms (GNENs) and establish a new tool to estimate the prognosis of gastric neuroendocrine carcinoma (GNEC) and gastric neuroendocrine tumor (GNET). METHODS: Nomograms were established based on a retrospective study on patients diagnosed with GNENs from 1975 to 2016 in Surveillance, Epidemiology and End Results database. External validation was performed among 246 GNENs patients in Jiangsu province to verify the discrimination and calibration of the nomograms. RESULTS: The age-adjusted incidence of GNENs has increased from 0.309 to 6.149 per 1,000,000 persons in the past 4 decades. Multivariate analysis indicated independent prognostic factors for both GNEC and GNET including age, distant metastasis and surgical intervention (P < 0.05). In addition, T, N staging and grade were significantly associated with survival of GNEC, while size was a predictor for GNET (P < 0.05). The C-indexes of the nomograms were 0.840 for GNEC and 0.718 for GNET, which were higher than those of the 8th AJCC staging system (0.773 and 0.599). Excellent discrimination was observed in the validation cohorts (C-index of nomogram vs AJCC staging for GNEC: 0.743 vs 0.714; GNET: 0.945 vs 0.927). Survival rates predicted by nomograms were close to the actual survival rates in the calibration plots in both training and validation sets. CONCLUSIONS: The incidence of the GNENs is increasing steadily in the past 40 years. We established more excellent nomograms to predict the prognosis of GNENs than traditional staging system, helping clinicians to make tailored decisions.
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Tumores Neuroendocrinos/epidemiología , Tumores Neuroendocrinos/patología , Nomogramas , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/patología , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/cirugía , Pronóstico , Estudios Retrospectivos , Programa de VERF , Neoplasias Gástricas/cirugía , Tasa de Supervivencia , Estados UnidosRESUMEN
It has been shown that long noncoding RNAs (lncRNAs) are involved in the carcinogenesis of multiple cancers. However, the roles of lncRNAs in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) remain elusive. In the present study, we found that lncNEN885 was markedly decreased in human gastric NEN samples compared to adjacent normal tissues by transcriptome sequencing. Functionally, silencing or overexpression of lncNEN885 could not obviously affect cell proliferation or apoptosis in BON-1 or LCC-18 cells but could affect cell migration and invasion as well as wound-healing rates. Furthermore, dysregulation of lncNEN885 affected these biological functions by activating epithelial-mesenchymal transition through increased expression of Snail, vimentin, and N-cadherin as well as decreased E-cadherin levels in BON-1 and LCC-18 cells. Silencing of lncNEN885 could dramatically increase the phosphorylation of glycogen synthase kinase-3ß and decrease the expression of adenomatous polyposis coli and Axin, with the subsequent accumulation of ß-catenin. Taken together, dysregulation of lncNEN885 can regulate cell migration and invasion by activating epithelial-mesenchymal transition process partially through canonical Wnt/ß-catenin signaling in GEP-NEN cells, which may be a novel biomarker for the metastasis of GEP-NENs.
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Transición Epitelial-Mesenquimal/genética , Neoplasias Gastrointestinales/genética , Regulación Neoplásica de la Expresión Génica , Tumores Neuroendocrinos/genética , Neoplasias Pancreáticas/genética , ARN Largo no Codificante/metabolismo , Apoptosis/genética , Movimiento Celular/genética , Proliferación Celular/genética , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/cirugía , Perfilación de la Expresión Génica , Humanos , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/cirugía , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Fosforilación , ARN Largo no Codificante/genética , ARN Interferente Pequeño , Estómago/patología , Vía de Señalización Wnt/genética , beta Catenina/metabolismoRESUMEN
Many autophagy-related genes, to our knowledge, have been identified as Crohn's disease (CD) polymorphic sites by genomic wide studies. As a novel member of the microtubule-associated protein 1 (MAP1) family, MAP1S is a microtubule-binding proteins involved in autophagy. However, its expression and potential functions in CD have not been understood. For the first time, we discovered the up-regulated MAP1S and autophagy level (indicated by LC3-â ¡/LC3-â ) in inflamed epithelium among CD patients. Similarly, in TNBS-induced murine colitis model, MAP1S expression was obviously increased. Meanwhile, we found the co-location of MAP1S and active-caspase 3 which acted as "apoptotic executor" which might indicate the basis of their co-efficient. At the cellular level, MAP1S silencing inhibited starvation-induced over-expression of active-caspase 3 partially via Wnt/ß-catenin signaling activation in HCT-116 cells. Finally, we demonstrated that IWP-2, an inhibitor of the Wnt/ß-catenin signaling, reversed the down-regulation of active-caspase 3 induced by MAP1S siRNA in HCT-116 cells. Taken together, our results suggested that MAP1S were up-regulated among CD patients and MAP1S-related autophagy inhibits apoptosis of intestinal epithelial cells (IECs) through Wnt/ß-catenin signaling pathway which might play a vital role in the protection of intestinal mucosal barrier and inhibition the progression of CD.
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Apoptosis/fisiología , Autofagia/fisiología , Enfermedad de Crohn/metabolismo , Células Epiteliales/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Vía de Señalización Wnt/fisiología , Animales , Benzotiazoles/farmacología , Western Blotting , Caspasa 3/metabolismo , Células Cultivadas , Colitis/inducido químicamente , Colitis/genética , Colitis/metabolismo , Enfermedad de Crohn/genética , Células HCT116 , Humanos , Inmunohistoquímica , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Ratones , Microscopía Confocal , Proteínas Asociadas a Microtúbulos/genética , Interferencia de ARN , Ácido Trinitrobencenosulfónico , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
Glycinamide ribonucleotide formyltransferase (GART) has been established as a pivotal enzyme in de novo purine synthesis, and mediates cellular apoptosis in many diseases. We aimed to investigate the role of GART in the pathogenesis of Crohn's disease (CD). In our study, we demonstrated for the first time that GART expression is up-regulated in patients with active CD and in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced acute colitis model. Moreover, the inhibition of GART induced cellular apoptosis and suppressed the migration of IECs through the activation of the MEKK3-MKK3-p38 mitogen-activated protein kinase (MAPK) pathway, following with the dys-regulation of p53 and p53 up-regulated modulator of apoptosis (PUMA). Taken together, GART plays a critical role in the protection of cellular apoptosis and migration of intestinal epithelial cells to maintain the integrity of the epithelial barrier, thus providing a new potential approach in designing a novel therapy for CD.
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Proteínas Reguladoras de la Apoptosis/metabolismo , Ligasas de Carbono-Nitrógeno/metabolismo , Colitis/metabolismo , Células Epiteliales/metabolismo , Mucosa Intestinal/metabolismo , Fosforribosilglicinamida-Formiltransferasa/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Apoptosis , Proteínas Reguladoras de la Apoptosis/genética , Ligasas de Carbono-Nitrógeno/genética , Proliferación Celular , Colitis/enzimología , Colitis/genética , Colitis/fisiopatología , Células Epiteliales/citología , Células Epiteliales/enzimología , Humanos , Intestinos/citología , Intestinos/enzimología , Sistema de Señalización de MAP Quinasas , Fosforribosilglicinamida-Formiltransferasa/genética , Proteínas Proto-Oncogénicas/genética , Proteína p53 Supresora de Tumor/genética , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
BACKGROUND: Pyruvate kinase M2 (PKM2), a key glycolytic enzyme, is involved in multiple cellular processes including apoptosis. Recently increased fecal PKM2 has been found in Crohn's disease (CD), but little is known regarding its function in the pathophysiology of the disease. AIM: The intestinal expression of PKM2 and its involvement in CD was investigated. METHODS: Pyruvate kinase M2 expression in mucosal biopsies from patients with CD and normal controls was detected by immunohistochemistry. A murine model of colitis induced by trinitrobenzenesulphonic acid (TNBS) was established and expression of PKM2, B cell lymphoma-extra large (Bcl-xl), active caspase-3 as well as cleaved poly (ADP-ribose) polymerase (PARP) was examined for association of PKM2 with intestinal epithelial cell (IEC) apoptosis. Furthermore, we treated human IEC line HT-29 by tumor necrosis factor-α (TNF-α) and used RNA interference to analyze the role of PKM2 in IEC apoptosis. RESULTS: Intestinal expression of PKM2 was higher in patients with CD compared with normal controls mainly locating in IECs. In TNBS-induced colitis, up-regulation of PKM2 was accompanied by the elevated expression of Bcl-xl, active caspase-3, and cleaved PARP. PKM2 was co-localized with active caspase-3 in IECs marked by E-cadherin, suggesting its role in IEC apoptosis. Expression of PKM2 and Bcl-xl in TNF-α-induced HT-29 cells was increased, while TNF-α had no effect on cellular localization of PKM2. Furthermore, knockdown of PKM2 by siRNA could inhibit expression of Bcl-xl but enhance apoptosis in TNF-α-treated HT-29 cells. CONCLUSION: The up-regulation of PKM2 might protect IECs against apoptosis possibly through Bcl-xl in CD, indicating its important role in the pathophysiology of CD.
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Apoptosis , Proteínas Portadoras/metabolismo , Colon/enzimología , Enfermedad de Crohn/enzimología , Células Epiteliales/enzimología , Mucosa Intestinal/enzimología , Proteínas de la Membrana/metabolismo , Piruvato Quinasa/metabolismo , Hormonas Tiroideas/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Portadoras/genética , Estudios de Casos y Controles , Colon/patología , Enfermedad de Crohn/inducido químicamente , Enfermedad de Crohn/patología , Modelos Animales de Enfermedad , Células Epiteliales/patología , Femenino , Células HT29 , Humanos , Mediadores de Inflamación/metabolismo , Mucosa Intestinal/patología , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos BALB C , Estudios Prospectivos , Piruvato Quinasa/genética , Interferencia de ARN , Transducción de Señal , Hormonas Tiroideas/genética , Factores de Tiempo , Transfección , Ácido Trinitrobencenosulfónico , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas de Unión a Hormona TiroideRESUMEN
The role of PIWI-interacting RNAs (piRNA) in small extracellular vesicles (sEV) derived from pancreatic neuroendocrine neoplasms (PNEN) in the tumor microenvironment (TME) remains unexplored. We used multiplex IHC to analyze the expression of CD68, CD276 (B7H3), and CD3 on PNEN. CD276+ tumor-associated macrophages (TAM) were more abundant in tumor tissues than nontumor tissues and negatively correlated with T-cell infiltration. Serum sEV piRNA sequencing was performed to identify piRNAs enriched in patients with PNEN. We then investigated the function and mechanism of sEV piR-hsa-30937 in the cross-talk between tumor cells and macrophages in the PNEN TME. PNEN-derived sEV piR-hsa-30937 targeted PTEN to activate the AKT pathway and drive CD276 expression. CD276+ macrophages inhibited T-cell proliferation and IFNγ production. piR-hsa-30937 knockdown and anti-CD276 treatment suppressed progression and metastasis in a preclinical model of PNEN by enhancing T-cell immunity. Thus, our data show that PNEN-derived sEV piR-hsa-30937 promotes CD276 expression in macrophages through the PTEN/AKT pathway and that CD276+ TAMs suppress T-cell antitumor immunity. sEV piR-hsa-30937 and CD276 are potential therapeutic targets for immunotherapy of PNEN.
Asunto(s)
Antígenos B7 , Vesículas Extracelulares , Macrófagos , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Antígenos B7/metabolismo , Antígenos B7/genética , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/inmunología , Tumores Neuroendocrinos/inmunología , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Animales , Ratones , Macrófagos/inmunología , Macrófagos/metabolismo , Microambiente Tumoral/inmunología , ARN Interferente Pequeño/genética , Femenino , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Línea Celular Tumoral , Masculino , Evasión Inmune , Regulación hacia Arriba , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Regulación Neoplásica de la Expresión GénicaRESUMEN
Tumor-associated macrophages (TAMs) represent a predominant cellular component within the tumor microenvironment (TME) of pancreatic neuroendocrine neoplasms (pNENs). There is a growing body of evidence highlighting the critical role of exosomes in facilitating communication between tumor cells and TAMs, thereby contributing to the establishment of the premetastatic niche. Nonetheless, the specific mechanisms through which exosomes derived from tumor cells influence macrophage polarization under hypoxic conditions in pNENs, and the manner in which these interactions support cancer metastasis, remain largely unexplored. Recognizing the capacity of exosomes to transfer miRNAs that can modify cellular behaviors, our research identified a significant overexpression of miR-4488 in exosomes derived from hypoxic pNEN cells. Furthermore, we observed that macrophages that absorbed circulating exosomal miR-4488 underwent M2-like polarization. Our investigations revealed that miR-4488 promotes M2-like polarization by directly targeting and suppressing RTN3 in macrophages. This suppression of RTN3 enhances fatty acid oxidation and activates the PI3K/AKT/mTOR signaling pathway through the interaction and downregulation of FABP5. Additionally, M2 polarized macrophages contribute to the formation of the premetastatic niche and advance pNENs metastasis by releasing MMP2, thereby establishing a positive feedback loop involving miR-4488, RTN3, FABP5, and MMP2 in pNEN cells. Together, these findings shed light on the role of exosomal miRNAs from hypoxic pNEN cells in mediating interactions between pNEN cells and intrahepatic macrophages, suggesting that miR-4488 holds potential as a valuable biomarker and therapeutic target for pNENs.
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Exosomas , Neoplasias Hepáticas , Macrófagos , MicroARNs , Tumores Neuroendocrinos , Neoplasias Pancreáticas , MicroARNs/metabolismo , MicroARNs/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Exosomas/metabolismo , Humanos , Animales , Ratones , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/genética , Macrófagos/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/genética , Línea Celular Tumoral , Ácidos Grasos/metabolismo , Oxidación-Reducción , Microambiente Tumoral , Proteínas de Unión a Ácidos Grasos/metabolismo , Proteínas de Unión a Ácidos Grasos/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Ratones Desnudos , Transducción de SeñalRESUMEN
In the process of determining positioning point by constructing geometric relations on the basis of the positions and poses obtained from multiple pairs of epipolar geometry, the direction vectors will not converge due to the existence of mixed errors. The existing methods to calculate the coordinates of undetermined points directly map the three-dimensional direction vector to the two-dimensional plane and take the intersection points that may be at infinity as the positioning result. To end this, an indoor visual positioning method with three-dimensional coordinates using built-in smartphone sensors based on epipolar geometry is proposed, which transforms the positioning problem into solving the distance from one point to multiple lines in space. It combines the location information obtained by the accelerometer and magnetometer with visual computing to obtain more accurate coordinates. Experimental results show that this positioning method is not limited to a single feature extraction method when the source range of image retrieval results is poor. It can also achieve relatively stable localization results in different poses. Furthermore, 90% of the positioning errors are lower than 0.58 m, and the average positioning error is less than 0.3 m, meeting the accuracy requirements for user localization in practical applications at a low cost.