RESUMEN
Colorectal cancer (CRC) is a multifaceted disease characterized by a complex interaction between tumor cells and the surrounding microenvironment. Within this intricate landscape, exosomes have emerged as pivotal players in the tumor-stroma crosstalk, influencing the immune microenvironment of CRC. These nano-sized vesicles, secreted by both tumoral and stromal cells, serve as molecular transporters, delivering a heterogeneous mix of biomolecules such as RNAs, proteins, and lipids. In the CRC context, exosomes exert dual roles: they promote tumor growth, metastasis, and immune escape by altering immune cell functions and activating oncogenic signaling pathways and offer potential as biomarkers for early CRC detection and treatment targets. This review delves into the multifunctional roles of exosomes in the CRC immune microenvironment, highlighting their potential implications for future therapeutic strategies and clinical outcomes.
Asunto(s)
Neoplasias Colorrectales , Exosomas , Humanos , Exosomas/metabolismo , ARN/metabolismo , Células del Estroma/metabolismo , Neoplasias Colorrectales/patología , Microambiente TumoralRESUMEN
Circular RNAs (circRNAs) play important roles in gastric cancer progression but the regulatory role of circRNAs in controlling macrophage function remains elusive. Exosomes serve as cargo for circRNAs and play a crucial role as mediators in facilitating communication between cancer cells and the tumor microenvironment. In this study, we found that circATP8A1, a previously unreported circular RNA, is highly expressed in both gastric cancer tissues and exosomes derived from plasma. Increased circATP8A1 was associated with advanced TNM stage and worse prognosis in patients with gastric cancer. We showed that the circATP8A1 knockdown significantly inhibited gastric cancer proliferation and invasion in vitro and in vivo. Functionally, exosome circATP8A1 induced the M2 polarization of macrophages through the STAT6 pathway instead of the STAT3 pathway. Mechanistically, circATP8A1 was shown to activate the STAT6 pathway through competitive binding to miR-1-3p, as confirmed by Fluorescence In Situ Hybridization (FISH), RNA immunoprecipitation, RNA pulldown, and Luciferase reporter assays. The reversal of circATP8A1-induced STAT6 pathway activation and macrophage polarization was observed upon blocking miR-1-3p. Macrophages treated with exosomes from gastric cancer cells overexpressing circATP8A1 were able to promote gastric cancer migration, while knockdown of circATP8A1 reversed these effects in vivo. In summary, exosome-derived circATP8A1 from gastric cancer cells induce macrophages M2 polarization via the circATP8A1/miR-1-3p/STAT6 axis, and tumor progression. Our results highlight circATP8A1 as a potential prognostic biomarker and therapeutic target in gastric cancer.
Asunto(s)
Exosomas , MicroARNs , Neoplasias Gástricas , Humanos , Línea Celular Tumoral , Proliferación Celular , Exosomas/genética , Hibridación Fluorescente in Situ , Macrófagos , MicroARNs/genética , ARN Circular/genética , Factor de Transcripción STAT6/genética , Neoplasias Gástricas/genética , Microambiente TumoralRESUMEN
Background: CAFs regulate the signaling of GC cells by promoting their migration, invasion, and proliferation and the function of immune cells as well as their location and migration in the TME by remodeling the extracellular matrix (ECM). This study explored the understanding of the heterogeneity of CAFs in TME and laid the groundwork for GC biomarker and precision treatment development. Methods: The scRNA-seq and bulk RNA-seq datasets were obtained from GEO and TCGA. The prognostic significance of various CAFs subtypes was investigated using ssGSEA combined with Kaplan-Meier analysis. POSTN expression in GC tissues and CAFs was detected using immunohistochemistry, immunofluorescence, and Western blotting. Differential expression analysis identified the differentially expressed genes (DEGs) between normal and tumor samples in TCGA-STAD. Pearson correlation analysis identified DEGs associated with adverse prognosis CAF subtype, and univariate Cox regression analysis determined prognostic genes associated with CAFs. LASSO regression analysis and Multivariate Cox regression were used to build a prognosis model for CAFs. Results: We identified five CAFs subtypes in GC, with the CAF_0 subtype associated with poor prognosis. The abundance of CAF_0 correlated with T stage, clinical stage, histological type, and immune cell infiltration levels. Periostin (POSTN) exhibited increased expression in both GC tissues and CAFs and was linked to poor prognosis in GC patients. Through LASSO and multivariate Cox regression analysis, three genes (CXCR4, MATN3, and KIF24) were selected to create the CAFs-score. We developed a nomogram to facilitate the clinical application of the CAFs-score. Notably, the CAFs signature showed significant correlations with immune cells, stromal components, and immunological scores, suggesting its pivotal role in the tumor microenvironment (TME). Furthermore, CAFs-score demonstrated prognostic value in assessing immunotherapy outcomes, highlighting its potential as a valuable biomarker to guide therapeutic decisions. Conclusion: CAF_0 subtype in TME is the cause of poor prognosis in GC patients. Furthermore, CAFs-score constructed from the CAF_0 subtype can be used to determine the clinical prognosis, immune infiltration, clinicopathological characteristics, and assessment of personalized treatment of GC patients.
RESUMEN
Background: Gastric cancer (GC) among adolescents and young adults (AYAs, aged 15-39 years) has limited data on clinicopathological characteristics and prognosis. This study aimed to compare the clinicopathological characteristics, perioperative outcomes, and long-term outcomes of AYAs and older adults (OAs, aged > 39 years) with GC who underwent curative gastrectomy. Methods: From January 1994 to June 2019, patients with GC undergoing curative gastrectomy were enrolled and divided into AYA group and OA group. The clinicopathological characteristics, treatment variables, perioperative outcomes and long-term outcomes were compared between the two groups, both before and after propensity score matching (PSM). Results: AYAs had fewer comorbid conditions and were more likely to be females, have normal carcinoembryonic antigen (CEA) levels, poorly differentiated tumors with perineural invasion, and receive adjuvant chemotherapy. AYA patients had lower incidence of postoperative complications and shorter length of postoperative hospital stay than OA patients. No significant differences in postoperative 30-day or 90-day mortality were observed between AYAs and OAs, both before and after PSM. In the entire cohort, AYAs had similar median overall survival (OS) to OAs. However, in the PSM cohort, AYAs had significantly shorter median OS. Young age (15-39 years) was an independent risk factor for OS in GC patients following gastrectomy. Conclusion: The clinicopathological characteristics were significantly different between AYA and OA patients with GC. AYA patients with GC had worse long-term prognosis than OA patients, and young age was an independent risk factor for OS in GC patients following gastrectomy.
RESUMEN
Background: Common kinds of soft tissue sarcomas (STS) include well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS). In this case, we present a comprehensive clinical profile of a patient who underwent multiple recurrences during the progression from WDLPS to DDLPS. Case presentation: A 62-year-old Asian female underwent retroperitoneal resection of a large tumor 11 years ago, the initial pathology revealed a fibrolipoma-like lesion. Over the next six years, the patient underwent three resections for recurrence of abdominal tumors. Postoperative histology shows mature adipose tissue with scattered "adipoblast"-like cells with moderate-to-severe heterogeneous spindle cells, pleomorphic cells, or tumor giant cells. Immunohistochemistry (IHC) demonstrated positive staining for MDM2 and CDK4, confirming that the abdominal tumor was WDLPS and gradually progressing to DDLPS. Post-operative targeted sequencing and IHC confirmed the POC1B::ROS1 fusion gene in DDLPS. Whole-exome sequencing (WES) revealed that WDLPS and DDLPS shared similar somatic mutations and copy number variations (CNVs), whereas DDLPS had more mutated genes and a higher and more concentrated amplification of the chromosome 12q region. Furthermore, somatic mutations in DDLPS were significantly reduced after treatment with CDK4 inhibitors, while CNVs remained elevated. Conclusion: Due to the high likelihood of recurrence of liposarcoma, various effective treatments should be taken into consideration even if surgery is the primary treatment for recurrent liposarcoma. To effectively control the course of the disease following surgery, combination targeted therapy may be a viable alternative to chemotherapy and radiotherapy in the treatment of liposarcoma.
RESUMEN
Background: Gastric cancer (GC) is one of the most prevalent cancers, and it has unsatisfactory overall treatment outcomes. DNA damage repair (DDR) is a complicated process for signal transduction that causes cancer. lncRNAs can influence the formation and incidence of cancers by influencing DDR-related mRNAs/miRNAs. A DDR-related lncRNA prognostic model is urgently needed to improve treatment strategies. Methods: The data of GC samples were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. A total of 588 mRNAs involved in DDR were selected from MSigDB, 62 differentially expressed mRNAs from TCGA-STAD were obtained, and 137 lncRNAs were correlated with these mRNAs. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were used to develop a DDR-related lncRNA prognostic model. Based on the risk model, the differentially expressed gene signature A/B in the low-risk and high-risk groups of TCGA-STAD was identified for further validation. Results: The prognosis model of 5 genes (AC145285.6, MAGI2-AS3, AL590705.3, AC007405.3, and LINC00106) was constructed and classified into two risk groups. We found that GC patients with a low-risk score had a better OS than those with a high-risk score. We found that the high-risk group tended to have higher TME scores. We also found that patients in the high-risk group had a higher proportion of resting CD4 T cells, monocytes, M2 macrophages, resting dendritic cells, and resting mast cells, whereas the low-risk subgroup had a greater abundance of activated CD4 T cells, follicular helper T cells, M0 macrophages, and M1 macrophages. We observed significant differences in the T-cell exclusion score, T-cell dysfunction, MSI, and TMB between the two risk groups. In addition, we found that patients treated with immunotherapy in the low-RS score group had a longer survival and a better prognosis than those in the high-RS score group. Conclusion: The prognostic model has a significant role in the TME, clinicopathological characteristics, prognosis, MSI, and drug sensitivity. We also discovered that patients treated with immunotherapy in the low-RS score group had a better prognosis. This work provides a foundation for improving the prognosis and response to immunotherapy among patients with GC.
Asunto(s)
ARN Largo no Codificante , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , ARN Largo no Codificante/genética , Pronóstico , Inmunoterapia , Daño del ADNRESUMEN
RNA-binding proteins (RBPs) play essential roles in tumorigenesis and progression, but their functions in gastric cancer (GC) remain largely elusive. Here, it is reported that Pumilio 1 (PUM1), an RBP, induces metabolic reprogramming through post-transcriptional regulation of DEP domain-containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR) in GC. In clinical samples, elevated expression of PUM1 is associated with recurrence, metastasis, and poor survival. In vitro and in vivo experiments demonstrate that knockdown of PUM1 inhibits the proliferation and metastasis of GC cells. In addition, RNA-sequencing and bioinformatics analyses show that PUM1 is enriched in the glycolysis gene signature. Metabolomics studies confirm that PUM1 deficiency suppresses glycolytic metabolism. Mechanistically, PUM1 binds directly to DEPTOR mRNA pumilio response element to maintain the stability of the transcript and prevent DEPTOR degradation through post-transcriptional pathway. PUM1-mediated DEPTOR upregulation inhibits mTORC1 and alleviates the inhibitory feedback signal transmitted from mTORC1 to PI3K under normal conditions, thus activating the PI3K-Akt signal and glycolysis continuously. Collectively, these results reveal the critical epigenetic role of PUM1 in modulating DEPTOR-dependent GC progression. These conclusions support further clinical investigation of PUM1 inhibitors as a metabolic-targeting treatment strategy for GC.
Asunto(s)
Transducción de Señal , Neoplasias Gástricas , Humanos , Fosfatidilinositol 3-Quinasas , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Gástricas/genética , Serina-Treonina Quinasas TOR/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismoRESUMEN
Introduction: Gastric cancer (GC) is the fifth frequent malignancy and is responsible for the third leading cause of cancer-related deaths. Gastric cancer is an aging-related disease, with incidence and mortality rates increasing with aging. The development of GC is affected by lncRNAs, miRNAs, and mRNAs at the transcriptional and posttranscriptional levels. This study aimed to establish a prognostic panel for GC based on competing endogenous RNA (ceRNA) networks. Methods: RNA sequences were obtained from the TCGA database. Different expressions of RNAs were scrutinized with the EdgeR package. The ceRNA network was built using the starBase database and the Cytoscape. The prognostic panel was constituted with the LASSO algorithm. We developed a nomogram comprising clinical characteristic and risk score. The receiver operating characteristic (ROC) was used to evaluate the accuracy of the nomogram prediction. Hub RNAs expressions were detected by qPCR, immunohistochemistry and western blot respectively. Clinical relevance and survival analyses were analyzed. The relationship between RNAs and immune infiltrations, as well as immune checkpoints, was analyzed and evaluated using the CIBERSORT, TIMER and TISIDB databases. Results: Four DElncRNAs, 21 DEmiRNAs and 45 DEmRNAs were included in the ceRNA network. A 3-element panel (comprising lncRNA PVT1, hsa-miR-130a-3p and RECK) with poor overall survival (OS) was established and qPCR was applied to validate the expressions of hub RNAs. Hub RNAs were firmly associated with T, M, and N stage. The CIBERSORT database showed that the high lassoScore group exhibited a significantly high ratio of resting memory CD4+ T cells, M2 macrophages and a significantly low ratio of activated memory CD4+ T cells and M1 macrophages. According to the TIMER database, this panel was linked to immune infiltrations and immune cell gene markers. TISIDB database indicated that RECK was positively correlated with immune checkpoints (including CD160, CD244, PDCD1, and TGFBR1). Discussion: A novel triple prognostic panel of GC constructed based on the ceRNA network was associated with clinical prognostic, clinicopathological features, immune infiltrations, immune checkpoints and immune gene markers. This panel might provide potential therapeutic targets for GC and more experimental verification research is needed.
RESUMEN
AIMS: Chemoresistance remains a major challenge in gastric cancer (GC). Chromodomain helicase DNA-binding protein 4 (CHD4) mediated chromatin remodeling plays critical roles in various tumor types, but its role in chemoresistance in GC remains uncharacterized. METHODS: CHD4 expression was examined by immunohistochemistry and Western blotting. The role of CHD4 on cell proliferation and chemoresistance of GC was examined in vitro and in vivo. Immunoprecipitation and liquid chromatography-mass spectrometry were used to identify CHD4-binding proteins and a proximity ligation assay was used to explore protein-protein interaction. RESULTS: Chemoresistance is associated with upregulation of CHD4 in the tumor tissues of GC patients. Overexpression of CHD4 increased chemoresistance and cell proliferation. Knockdown of CHD4 induced cell apoptosis and cell cycle arrest. CHD4 mediates the decrease of the intracellular concentration of cisplatin by inducing drug efflux. Additionally, CHD4 promotes the interaction between ERK1/2 and MEK1/2, resulting in continuous activation of MEK/ERK pathway. Knockdown of CHD4 in GC increased sensitivity to chemotherapy and suppressed tumor growth in a mouse xenograft model. CONCLUSIONS: This study identifies CHD4 dominated multi-drug efflux as a promising therapeutic target for overcoming acquired chemoresistance in GC.
Asunto(s)
Cisplatino , Resistencia a Antineoplásicos , Animales , Humanos , Ratones , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Cisplatino/farmacología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2 , Quinasas de Proteína Quinasa Activadas por Mitógenos , Quinasas MAP Reguladas por Señal Extracelular/metabolismoRESUMEN
O-glycosylation is a widespread post-translational modification of proteins. Aberrant O-glycosylation is a hallmark of cancer. Here, we show that the polypeptide N-acetylgalactosamine-transferase 1 (GALNT1) is frequently upregulated in gastric cancer and is correlated with poor survival. Overexpression of GALNT1 promoted, whereas knockdown suppressed proliferation, migration, and invasion of gastric cancer cells in vitro and in vivo. Mechanistically, GALNT1 enhances aberrant initiation of O-glycosylation and results in CD44 glycoproteins modified with abundant Tn antigens, thereby activating the Wnt/ß-catenin signaling pathway. Collectively, this study demonstrates that GALNT1 overexpression in gastric cancer promotes the Wnt/ß-catenin signaling pathway via abnormal O-glycosylation of CD44 to enhance malignancy, providing a novel strategy for the development of therapeutic reagents against gastric cancer.
Asunto(s)
Neoplasias Gástricas , Vía de Señalización Wnt , Humanos , Vía de Señalización Wnt/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Glicosilación , Fenotipo , Receptores de Hialuranos/genéticaRESUMEN
OBJECTIVE: Branched-chain amino acids (BCAAs) are popular dietary supplements for exercise. However, increased BCAA levels positively correlate with obesity and diabetes. The metabolic impact of BCAA supplementation on insulin sensitivity during exercise is less understood. METHODS: Male C57BL/6 mice were fed for 12 weeks with a high-fat diet, normal chow diet, or BCAA-restricted high-fat diet. They were subjected to running exercise with or without BCAA treatment for another 12 weeks. RESULTS: Exercise reduced body weight, improved insulin sensitivity, lowered BCAAs in plasma, and inhibited the upregulation of BCAAs and metabolites caused by BCAA supplementation in the subcutaneous white adipose tissue (sWAT) of obese mice. BCAA supplementation reversed insulin sensitivity ameliorated by exercise. The phosphorylation of protein kinase B (Ser473 and Ser474) was decreased by BCAAs in the sWAT of obese mice. However, BCAA supplementation had no such effects in lean mice. BCAAs also increased the expression of fatty acid synthase and other lipogenesis genes in the sWAT of exercised obese mice. BCAA restriction had no effect on body weight and insulin sensitivity in obese mice. CONCLUSIONS: BCAA supplementation impaired the beneficial effect of exercise on glycolipid metabolism in obese but not lean mice. Caution should be taken regarding the use of BCAAs for individuals with obesity who exercise.
Asunto(s)
Resistencia a la Insulina , Aminoácidos de Cadena Ramificada , Animales , Peso Corporal , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos , Lipogénesis , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/tratamiento farmacológico , Obesidad/metabolismoRESUMEN
Syntaxin-6 (STX6), a vesicular transport protein, is a direct target of the tumor suppressor gene P53, supporting cancer growth dependent on P53. However, STX6's function in the tumor microenvironment has yet to be reported. In this research, we comprehensively explored the role of the oncogene STX6 in pan-cancer by combining data from several databases, including the Cancer Genome Atlas, CPTAC, cBioPortal, and TIMER. Then, we verified the carcinogenic effect of STX6 in hepatocellular carcinoma (HCC) and colorectal cancer (CRC) through a series of experiments in vitro and in vivo. Bioinformatics analysis demonstrated that STX6 is an oncogene for several cancers and is mainly involved in the cell cycle, epithelial-mesenchymal transition, oxidative phosphorylation, and tumor immune modulation, especially for tumor-associated fibroblasts (CAFs) and NKT cells. Additionally, a high level of STX6 could indicate patients' resistance to immunotherapy. Our own data indicated that the STX6 level was upregulated in HCC and CRC. Knockdown of the STX6 levels could arrest the cell cycle and restrain cell proliferation, migration, and invasion. RNA-seq indicated that STX6 was significantly involved in pathways for cancer, such as the MAPK signal pathway. In a mouse model, knockdown of STX6 inhibited tumor growth and potentiated anti-PD-1 efficacy. In light of the essential roles STX6 plays in carcinogenesis and cancer immunology, it has the potential to be a predictive biomarker and a target for cancer immunotherapy.
RESUMEN
An online field observation was conducted in Zibo, China from September 1, 2018 to February 28, 2019, covering autumn and winter. Within the investigation period, the mean mass concentrations of PM1, PM2.5, and PM10 were 49.3, 86.1, and 136.5 µg m-3, respectively. OA (organic aerosol) was the most dominant species in PM2.5 (39.7 %), followed by NO3- (26.3 %) and SO42- (17.0 %), indicating the importance of secondary species on PM2.5. Increase of particles were always accompanied increasing relative humidity (RH), slow wind, and increasing precursors, contributing the secondary transition. SO42- was more susceptible to RH, indicating the dominant role of heterogeneous processes in its secondary formation. As RH increased, its strengthening effect on SO42- increased as well. Photochemistry was the main contributor to the secondary formation of NO3-. The morning and evening rush hours determined the peak of absolute NO3- throughout the day. By classifying particles into three bins, we found that smaller particles were the biggest contributors (larger PM1/PM2.5) of slight pollution (35 < PM2.5<115 µg m-3). When severe haze occurred, PM2.5 contributed more than particles of other sizes (PM1 or PM10). Secondary species contributed more to particles within 2.5 µm but less to larger particles. PM1/PM2.5 was high from 9:00 to 15:00, indicating the strong effect of photochemistry on smaller particles. In comparison, larger particles favored more humid conditions. NO3- preferentially existed in larger particles because the hygroscopicity of preexisting species (SO42- and NO3-) promoted partitioning. SO42- appeared a stable diurnal variation, replying its stable contribution to particles of different sizes.
Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Aerosoles/análisis , Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , China , Monitoreo del Ambiente , Material Particulado/análisis , Estaciones del AñoRESUMEN
AIMS: In addition to its involvement of inflammatory responses, limited information is available on the phenotype and behaviour of vascular macrophages during hypertensive vascular remodelling. Here, we aim at studying the contribution of BMAL1 to the pro-fibrotic macrophage phenotype in the vasculature during hypertension, which leads to enhanced vascular remodelling and promoted blood pressure increase. METHODS AND RESULTS: Wild type Bmal1f/f and myeloid cell selective Bmal1 knockout Bmal1f/f; LysMCre/+ mice were infused with AngII for 4 weeks to induce hypertension. AngII-induced blood pressure increase, vascular media thickness and vascular dysfunction were enhanced in Bmal1f/f; LysMCre/+ mice, accompanied with a pro-fibrotic M2 phenotype of the vascular macrophages. Bmal1f/f; LysMCre/+ mice also have more up-regulations of MMP9 and MMP13 expression in the vascular wall, accompanied by enhanced collagen deposition after AngII infusion. Loss of Bmal1 in bone marrow-derived macrophages enhanced STAT6 activation induced by IL4, and the subsequent MMP13 up-regulation and activity. In macrophages, loss of Bmal1 enhanced the phosphorylation and nuclear translocation of STAT6 triggered by IL4, through possibly a direct interaction between BMAL1 and STAT6. To further determine whether IL4-induced signalling in macrophage contributes to enhanced vascular remodelling in hypertensive mice, we showed that deletion of myeloid IL4Rα in Il4raf/f; LysMCre/+ mice attenuated blood pressure increase and hypertensive vascular remodelling after AngII infusion. CONCLUSIONS: Our results suggested a tonic effect of BMAL1 deletion on hypertensive vascular remodelling. BMAL1 might inhibit IL4-STAT6 signalling in macrophages through the interaction with STAT6 to reduce STAT6 activation and target gene transcription, especially MMP9 and MMP13, contributing to vascular remodelling.
Asunto(s)
Factores de Transcripción ARNTL , Hipertensión , Factor de Transcripción STAT6 , Remodelación Vascular , Animales , Ratones , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Hipertensión/metabolismo , Interleucina-4/metabolismo , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción STAT6/genética , Factor de Transcripción STAT6/metabolismoRESUMEN
Chemotherapy plays an irreplaceable role in the treatment of GC, but currently available chemotherapeutic drugs are not ideal. The application of medicinal plants is an important direction for new drug discovery. Through drug screening of GC organoids, we determined that ailanthone has an anticancer effect on GC cells in vitro and in vivo. We also found that AIL can induce DNA damage and apoptosis in GC cells. Further transcriptome sequencing of PDX tissue indicated that AIL inhibited the expression of XRCC1, which plays an important role in DNA damage repair, and the results were also confirmed by western blotting. In addition, we found that AIL inhibited the expression of P23 and that inhibition of P23 decreased the expression of XRCC1, indicating that AIL can regulate XRCC1 via P23. The results of coimmunoprecipitation showed that AIL can inhibit the binding of P23 and XRCC1 to HSP90. These findings indicate that AIL can induce DNA damage and apoptosis in GC cells. Meanwhile, AIL can decrease XRCC1 activity by downregulating P23 expression to inhibit DNA damage repair. The present study sheds light on the potential application of new drugs isolated from natural medicinal plants for GC therapy.
Asunto(s)
Apoptosis/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Piridinolcarbamato/metabolismo , Cuassinas/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Ailanthus/química , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Regulación hacia Abajo , Descubrimiento de Drogas , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Gástricas/metabolismo , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Oxaliplatin is one of the most commonly used chemotherapeutic agent for the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Hence, it is of great significance to develop novel therapies to potentiate the anti-tumor effect and reduce the toxicity of oxaliplatin. In our previous study, we demonstrated that ethaselen (BBSKE), an inhibitor of thioredoxin reductase, effectively inhibited the growth of gastric cancer cells and promoted apoptosis in vitro. In the present study, we investigated whether BBSKE can potentiate the anti-tumor effect of oxaliplatin in gastric cancer in vivo and vitro. METHODS: Cellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells, organoid and tumor tissues was determined by using the endpoint insulin reduction assay. Western blot was used to analyze the expressions of the indicated proteins. Nude mice xenograft models were used to test the effects of BBSKE and oxaliplatin combinations on gastric cancer cell growth in vivo. In addition, we also used the combined treatment of BBSKE and oxaliplatin in three cases of gastric cancer Patient-Derived organoid (GC-PDO) to detect the anti-tumor effect. RESULTS: We found that BBSKE significantly enhanced oxaliplatin-induced growth inhibition in gastric cancer cells by inhibiting TrxR1 activity. Because of the inhibition of TrxR1 activity, BBSKE synergized with oxaliplatin to enhance the production of ROS and activate p38 and JNK signaling pathways which eventually induced apoptosis of gastric cancer cells. In vivo, we also found that BBSKE synergized with oxaliplatin to suppress the gastric cancer tumor growth in xenograft nude mice model, accompanied by the reduced TrxR1 activity. Remarkably, we found that BBSKE attenuated body weight loss evoked by oxaliplatin treatment. We also used three cases of GC-PDO and found that the combined treatment of BBSKE and oxaliplatin dramatically inhibited the growth and viability of GC-PDO with increased ROS level, decreased TrxR1 activity and enhanced apoptosis. CONCLUSIONS: This study elucidates the underlying mechanisms of synergistic effect of BBSKE and oxaliplatin, and suggests that the combined treatment has potential value in gastric cancer therapy.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos de Organoselenio/farmacología , Oxaliplatino/farmacología , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Gástricas/metabolismo , Tiorredoxina Reductasa 1/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Activación Enzimática , Humanos , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Desnudos , Organoides , Neoplasias Gástricas/etiología , Neoplasias Gástricas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
N6-methyladenosine (m6A) is a well-known modification of RNA. However, as a key m6A methyltransferase, METTL16 has not been thoroughly studied in gastric cancer (GC). Here, the biological role of METTL16 in GC and its underlying mechanism was studied. Immunohistochemistry was used to detect the expression of METTL16 and relationship between METTL16 level and prognosis of GC was analysed. CCK8, colony formation assay, EdU assay and xenograft mouse model were used to study the effect of METTL16. Regulatory mechanism of METTL16 in the progression of GC was studied through flow cytometry analysis, RNA degradation assay, methyltransferase inhibition assay, RT-qPCR and Western blotting. METTL16 was highly expressed in GC cells and tissues and was associated with prognosis. In vitro and in vivo experiments confirmed that METTL16 promoted proliferation of GC cells and tumour growth. Furthermore, down-regulation of METTL16 inhibited proliferation by G1/S blocking. Significantly, we identified cyclin D1 as a downstream effector of METTL16. Knock-down METTL16 decreased the overall level of m6A and the stability of cyclin D1 mRNA in GC cells. Meanwhile, inhibition of methyltransferase activity reduced the level of cyclin D1. METTL16-mediated m6A methylation promotes proliferation of GC cells through enhancing cyclin D1 expression.
Asunto(s)
Proliferación Celular/genética , Ciclina D1/genética , Metiltransferasas/genética , Neoplasias Gástricas/genética , Adenosina/genética , Adulto , Anciano , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Xenoinjertos , Humanos , Masculino , Metilación , Ratones , Persona de Mediana Edad , Pronóstico , Estabilidad del ARN/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
To control the spread of COVID-19, China implemented a series of lockdowns, limiting various offline interactions. This provided an opportunity to study the response of air quality to emissions control. By comparing the characteristics of pollution in the summers of 2019 and 2020, we found a significant decrease in gaseous pollutants in 2020. However, particle pollution in the summer of 2020 was more severe; PM2.5 levels increased from 35.8 to 44.7 µg m-3, and PM10 increased from 51.4 to 69.0 µg m-3 from 2019 to 2020. The higher PM10 was caused by two sandstorm events on May 11 and June 3, 2020, while the higher PM2.5 was the result of enhanced secondary formation processes indicated by the higher sulfate oxidation rate (SOR) and nitrate oxidation rate (NOR) in 2020. Higher SOR and NOR were attributed mainly to higher relative humidity and stronger oxidizing capacity. Analysis of PMx distribution showed that severe haze occurred when particles within Bin2 (size ranging 1-2.5 µm) dominated. SO42-(1/2.5) and SO42-(2.5/10) remained stable under different periods at 0.5 and 0.8, respectively, indicating that SO42- existed mainly in smaller particles. Decreases in NO3-(1/2.5) and increases in NO3-(2.5/10) from clean to polluted conditions, similar to the variations in PMx distribution, suggest that NO3- played a role in the worsening of pollution. O3 concentrations were higher in 2020 (108.6 µg m-3) than in 2019 (96.8 µg m-3). Marked decreases in fresh NO alleviated the titration of O3. Furthermore, the oxidation reaction of NO2 that produces NO3- was dominant over the photochemical reaction of NO2 that produces O3, making NO2 less important for O3 pollution. In comparison, a lower VOC/NOx ratio (less than 10) meant that Beijing is a VOC-limited area; this indicates that in order to alleviate O3 pollution in Beijing, emissions of VOCs should be controlled.
Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , COVID-19 , Aerosoles/análisis , Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , Beijing , China , Control de Enfermedades Transmisibles , Monitoreo del Ambiente , Gases , Humanos , Material Particulado/análisis , SARS-CoV-2 , Estaciones del AñoRESUMEN
AIMS: Disturbed blood flow at arterial branches and curvatures modulates endothelial function and predisposes the region to endothelial inflammation and subsequent development of atherosclerotic lesions. Activation of the endothelial Toll-like receptors (TLRs), in particular TLR4, contributes to vascular inflammation. Therefore, we investigate whether TLR4 can sense disturbed flow (DF) to mediate the subsequent endothelial inflammation. METHODS AND RESULTS: En face staining of endothelium revealed that TLR4 expression, activation, and its downstream inflammatory markers were elevated in mouse aortic arch compared with thoracic aorta, which were absent in Tlr4mut mice. Similar results were observed in the partial carotid ligation model where TLR4 signalling was activated in response to ligation-induced flow disturbance in mouse carotid arteries, and such effect was attenuated in Tlr4mut mice. DF in vitro increased TLR4 expression and activation in human endothelial cells (ECs) and promoted monocyte-EC adhesion, which were inhibited in TLR4-knockdown ECs. Among endogenous TLR4 ligands examined as candidate mediators of DF-induced TLR4 activation, fibronectin containing the extra domain A (FN-EDA) expressed by ECs was increased by DF and was revealed to directly interact with and activate TLR4. CONCLUSION: Our findings demonstrate the indispensable role of TLR4 in DF-induced endothelial inflammation and pinpoint FN-EDA as the endogenous TLR4 activator in this scenario. This novel mechanism of vascular inflammation under DF condition may serve as a critical initiating step in atherogenesis.