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BACKGROUND: Traditional nanodrug delivery systems have some limitations, such as eliciting immune responses and inaccuracy in targeting tumor microenvironments. MATERIALS AND METHODS: Targeted drugs (Sorafenib, Sora) nanometers (hollow mesoporous silicon, HMSN) were designed, and then coated with platelet membranes to form aPD-1-PLTM-HMSNs@Sora to enhance the precision of drug delivery systems to the tumor microenvironment, so that more effective immunotherapy was achieved. RESULTS: These biomimetic nanoparticles were validated to have the same abilities as platelet membranes (PLTM), including evading the immune system. The successful coating of HMSNs@Sora with PLTM was corroborated by transmission electron microscopy (TEM), western blot and confocal laser microscopy. The affinity of aPD-1-PLTM-HMSNs@Sora to tumor cells was stronger than that of HMSNs@Sora. After drug-loaded particles were intravenously injected into hepatocellular carcinoma model mice, they were demonstrated to not only directly activate toxic T cells, but also increase the triggering release of Sora. The combination of targeted therapy and immunotherapy was found to be of gratifying antineoplastic function on inhibiting primary tumor growth. CONCLUSIONS: The aPD-1-PLTM-HMSNs@Sora nanocarriers that co-delivery of aPD-1 and Sorafenib integrates unique biomimetic properties and excellent targeting performance, and provides a neoteric idea for drug delivery of personalized therapy for primary hepatocellular carcinoma (HCC).
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Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Animales , Ratones , Sorafenib/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Biomimética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Microambiente TumoralRESUMEN
BACKGROUND: Circulating tumor cells (CTCs) can adsorb and activate platelets to form a microthrombus protective barrier around them, so that therapeutic drugs and immune cells cannot effectively kill CTCs. The platelet membrane (PM) bionic carrying drug system has the powerful ability of immune escape, and can circulate in the blood for a long time. MATERIALS AND METHODS: we developed platelet membrane coated nanoparticles (PM HMSNs) to improve the precise delivery of drugs to tumor sites and to achieve more effective immunotherapy combined with chemotherapy strategy. RESULTS: Successfully prepared aPD-L1-PM-SO@HMSNs particles, whose diameter is 95-130 nm and presenting the same surface protein as PM. Laser confocal microscopy and flow cytometry experimental results showed that the fluorescence intensity of aPD-L1-PM-SO@HMSNs was greater than SO@HMSNs that are not coated by PM. Biodistribution studies in H22 tumor-bearing mice showed that due to the combined action of the active targeting effect and the EPR effect, the high accumulation of aPD-L1-PM-SO@HMSNs in the local tumor was more effective in inhibiting tumor growth than other groups of therapeutic agents. CONCLUSION: Platelet membrane biomimetic nanoparticles have a good targeted therapeutic effect, which can effectively avoid immune clearance and have little side effects. It provides a new direction and theoretical basis for further research on targeted therapy of CTCs in liver cancer.
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Nanopartículas , Células Neoplásicas Circulantes , Animales , Ratones , Sorafenib , Plaquetas/metabolismo , Anticuerpos Monoclonales/metabolismo , Antígeno B7-H1/metabolismo , Distribución Tisular , Línea Celular TumoralRESUMEN
BACKGROUND: Increasing evidence suggests that taurine upregulated gene 1 (TUG1) is crucial for tumor progression; however, its role in hepatocellular carcinoma (HCC) and the underlying mechanisms are not well characterized. METHODS: The expression levels of TUG1, miR-524-5p, and sine oculis homeobox homolog 1 (SIX1) were determined using quantitative real-time PCR. The regulatory relationships were confirmed by dual-luciferase reporter assay. Cell proliferation and invasion were assessed using Cell Counting Kit 8 and transwell assays. Glucose uptake, cellular levels of lactate, lactate dehydrogenase (LDH), and adenosine triphosphate (ATP) were detected using commercially available kits. Silencing of TUG1 or SIX1 was performed by lentivirus transduction. Protein levels were measured by immunoblotting. RESULTS: Cancer-associated fibroblasts (CAFs)-secreted exosomes promoted migration, invasion, and glycolysis in HepG2 cells by releasing TUG1. The promotive effects of CAFs-secreted exosomes were attenuated by silencing of TUG1. TUG1 and SIX1 are targets of miR-524-5p. SIX1 knockdown inhibited the promotive effects of miR-524-5p inhibitor. Silencing of TUG1 suppressed tumor growth and lung metastasis and therefore increased survival of xenograft model mice. We also found that TUG1 and SIX1 were increased in HCC patients with metastasis while miR-524-5p was decreased in HCC patients with metastasis. CONCLUSIONS: CAFs-derived exosomal TUG1 promoted migration, invasion, and glycolysis in HCC cells via the miR-524-5p/SIX1 axis. These findings may help establish the foundation for the development of therapeutics strategies and clinical management for HCC in future.
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Fibroblastos Asociados al Cáncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , ARN Largo no Codificante , Animales , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Glucólisis , Proteínas de Homeodominio/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Transducción de Señal , TaurinaRESUMEN
BACKGROUND: Gemcitabine is the first-line chemotherapy drug that can easily cause chemotherapy resistance. Huaier is a traditional Chinese medicine and shows an antitumor effect in pancreatic cancer, but whether it can enhance the gemcitabine chemotherapeutic response and the potential mechanism remain unknown. PURPOSE: This study was performed to explore the effect of Huaier in promoting the tumor-killing effect of gemcitabine and elucidate the possible mechanism in pancreatic cancer. METHODS: Cell Counting Kit-8 assays and colony formation assays were used to detect proliferation after different treatments. Protein coimmunoprecipitation was applied to demonstrate protein interactions. Nuclear protein extraction and immunofluorescence were used to confirm the intracellular localization of the proteins. Western blotting was performed to detect cell proliferation-related protein expression or cancer stem cell-associated protein expression. Sphere formation assays and flow cytometry were used to assess the stemness of pancreatic cancer cells. The in vivo xenograft model was used to confirm the inhibitory effect under physiological conditions, and immunohistochemistry was used to detect protein expression. RESULTS: Huaier suppressed the proliferation and stem cell-like properties of pancreatic cancer cells. We found that Huaier suppressed the expression of forkhead box protein M1 (FoxM1). In addition, Huaier inhibited FoxM1 function by blocking its nuclear translocation. Treatment with Huaier reversed the stemness induced by gemcitabine in a FoxM1-dependent manner. Furthermore, we verified the above results by an in vivo study, which reached the same conclusion as those in vitro. CONCLUSION: Overall, this study illustrates that Huaier augments the tumor-killing effect of gemcitabine through suppressing the stemness induced by gemcitabine in a FoxM1-dependent way. These results indicate that Huaier can be applied to overcome gemcitabine resistance.
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Proliferación Celular , Desoxicitidina , Proteína Forkhead Box M1 , Gemcitabina , Ratones Desnudos , Células Madre Neoplásicas , Neoplasias Pancreáticas , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Proteína Forkhead Box M1/metabolismo , Humanos , Animales , Neoplasias Pancreáticas/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de Xenoinjerto , Medicamentos Herbarios Chinos/farmacología , Mezclas Complejas , TrametesRESUMEN
The emergence of targeted drugs brings hope to patients with advanced liver cancer. However, due to the complex and diverse environment in the human body, the overall response rate of targeted drugs is not high. Therefore, how to efficiently deliver targeted drugs to tumor sites is a major challenge for current research. The project intends to construct mPEG-PLGA nanoparticles loaded with Sora and encapsulate them with exosomes for targeted therapy of hepatocellular carcinoma. mPEG-PLGA drug-loaded nanoparticles were prepared by the dialysis method and characterized by TEM and DLS. The obtained nanoparticles were incubated with the exosomes of liver cancer cells, and the exosomes-encapsulated drug-loaded nanoparticles (Exo-Sora-NPs) were obtained under pulsed ultrasound conditions, and they were characterized by Western blot, transmission electron microscopy (TEM), and dynamic light scattering (DLS). The toxic effect of Exo-Sora-NPs on liver cancer cells was detected by the CCK-8 experiment. The uptake efficiency of nanoparticles by liver cancer cells was detected by a confocal microscope. The accumulation and infiltration depth of nanomedicine in liver cancer tissues were observed by confocal microscope on frozen sections of liver cancer tissue after the H22 liver cancer subcutaneous tumor transplantation model was constructed. The tumor size, body weight, pathology, and serology analysis of mice were measured after administration. The mPEG-PLGA polymer drug-loaded particles encapsulated by exosomes have high targeting ability and biosafety. To a certain extent, they can target the drug to the tumor site with a smaller systemic response and have a highly effective killing effect on the tumor. Nanodrug-loaded particles encapsulated by exosomes have great potential as drug carriers.
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Endometrial cancer (EC) kills about 76,000 women worldwide, with the highest incidence in industrialized countries. Because of the rise in disease mortality and new diagnoses, EC is now a top priority for women's health. Serine racemase (SRR) is thought to play a role in the central nervous system, but its role in cancers, particularly in EC, is largely unknown. The current study starts with a pan-cancer examination of SRR's expression and prognostic value before delving into SRR's potential cancer-suppressing effect in patients with EC. SRR may affect the endometrial tumor immune microenvironment, according to subsequent immune-related analysis. SRR expression is also linked to several genes involved in specific pathways such as ferroptosis, N6-methyladenosine methylation, and DNA damage repair. Finally, we used the expression, correlation, and survival analyses to investigate the upstream potential regulatory non-coding RNAs of SRR. Overall, our findings highlight the prognostic significance of SRR in patients with EC, and we can formulate a reasonable hypothesis that SRR influences metabolism and obstructs key carcinogenic processes in EC.
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Accumulating studies have revealed that necroptosis plays a vital role in the occurrence and development of pancreatic adenocarcinoma (PAAD). We aimed to construct a prognostic model for PAAD on the basis of necroptosis-related lncRNAs (NRLs). A coexpression network between necroptosis-related mRNAs and NRLs based on The Cancer Genome Atlas (TCGA) was constructed. Then, differentially expressed necroptosis-related lncRNAs (DENRLs) were screened from TCGA and Genotype-Tissue Expression project (GTEx) datasets. Univariate Cox regression (uni-Cox) analysis was performed on these DENRLs to identify lncRNAs significantly correlated with prognosis. Least absolute shrinkage and selection operator (LASSO) regression was performed for preventing overfitting on these lncRNAs. Multivariate Cox analysis (multi-Cox) was performed to establish a risk model based on lncRNAs that served as an independent prognostic factor. Next, the Kaplan-Meier analysis, time-dependent receiver operating characteristics (ROC), uni-Cox, multi-Cox regression, nomogram, and calibration curves were constructed to support the accuracy of the model. Gene set enrichment analysis (GSEA) and single-sample GSEA (ssGSEA) were also performed on risk groups, and it was found that the low-risk group was closely correlated with immune infiltration and immunotherapy. To further evaluate the immune differences between different clusters, we divided the patients into two clusters. Cluster 2 was more significantly infiltrated with immune cells and had higher immune scores. These results shed new light on the pathogenesis of PAAD based on NRLs and develop a prognostic model for diagnosing and guiding personalized immunotherapy of PAAD patients.
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Anillin (ANLN) is a unique scaffolding, actin-binding protein, which is essential for the integrity and ingression of the cleavage furrow. It is mainly involved in the cytokinesis process, while its role in various tumors has not been fully addressed and remains largely elusive. To provide a thorough perspective of ANLN's roles among diverse malignancies, we conducted a comprehensive, pan-cancer analysis about ANLN, including but not limited to gene expression levels, prognostic value, biological functions, interacting proteins, immune-related analysis, and predictive value. As a result, when compared to normal tissues, ANLN expression is elevated in most cancers, and its expression also differs in different immune subtypes and molecular subtypes in diverse cancers. In addition, in 17 types of cancer, ANLN expression is increased in early tumor stages, and higher ANLN expression predicts worse survival outcomes in more than ten cancers. Furthermore, ANLN shows close correlations with the infiltration levels of most immune cells, and enrichment analysis using ANLN co-expressed genes reveals that ANLN plays essential roles in cell cycle, mitosis, cellular senescence, and p53 signaling pathways. In the final, ANLN exhibits high accuracy in predicting many cancers, and subsequent multivariate analysis suggests ANLN could be an independent prognostic factor in specific cancer types. Taken together, ANLN is proved to be a novel and promising biomarker for its excellent predictive utility, promising prognostic value, and potential immunological roles in pan-cancer. Targeting ANLN might be an attractive approach to tumor treatment.
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Ferroptosis is a new form of regulated cell death that is mediated by intracellular iron and ester oxygenase, and glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into nontoxic lipid alcohols. Although thiostrepton (TST) has been reported to exert antitumor effects, its role in pancreatic cancer and the underlying mechanisms remain unclear. In this study, we found that TST reduced the viability and clonogenesis of pancreatic cancer cell lines, along with intracellular iron overload, increasing reactive oxygen species (ROS) accumulation, malondialdehyde (MDA) overexpression, and glutathione peroxidase (GSH-PX) depletion. Mechanistically, chromatin immunoprecipitation (ChIP) and dual luciferase reporter gene assays were used to confirm that signal transducer and activator of transcription 3 (STAT3) binds to the GPX4 promoter region and promotes its transcription, whereas TST blocked GPX4 expression by regulating STAT3. Finally, in vivo experiments revealed that TST inhibited the growth of subcutaneously transplanted tumours and had considerable biosafety. In conclusion, our study identified the mechanism by which TST-induced ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling.