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Cellular iron is inseparably related with the proper functionalities of mitochondria for its potential to readily donate and accept electrons. Though promising, the available endeavors of iron chelation antitumor therapies have tended to be adjuvant therapies. Herein, we conceptualized and fabricated an "iron-phagy" nanoparticle (Dp44mT@HTH) capable of inducing the absolute devastation of mitochondria via inhibiting the autophagy-removal of impaired ones for promoting cancer cell death. The Dp44mT@HTH with hyaluronic acid (HA) as hydrophilic shell can specifically target the highly expressed CD44 receptors on the surface of 4T1 tumor cells. After internalization and lysosomal escape, the nanoparticle disassembles in response to the reactive oxygen species (ROS), subsequently releasing the iron chelator Dp44mT and autophagy-inhibitory drug hydroxychloroquine (HCQ). Dp44mT can then seize cellular Fe2+ to trigger mitochondrial dysfunction via respiratory chain disturbance, while HCQ not only lessens Fe2+ intake, but also impedes fusions of autophagosomes and lysosomes. Consequentially, Dp44mT@HTH induces irreversible mitochondrial impairments, in this respect creating a substantial toxic stack state that induces apoptosis and cell death. Initiating from the perspective of endogenous substances, this strategy illuminates the promise of iron depletion therapy via irreversible mitochondrial damage induction for anticancer treatment.
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Infantile hemangioma (IH) is the most common benign tumor in infants and usually resolves on its own. However, a small portion of IH cases are accompanied by serious complications and other problems, impacting the physical and psychological health of the children affected. The pathogenesis of IH is highly controversial. Studies have shown that abnormal blood vessel formation is an important pathological basis for the development of IH. Compared with that in normal tissues, the equilibrium of blood vessel growth at the tumor site is disrupted, and interactions among other types of cells, such as immune cells, promote the rapid proliferation and migration of vascular tissue cells and the construction of vascular networks. Currently, propranolol is the most common systemic drug used to inhibit the growth of IHs and accelerate their regression. The purpose of this review is to provide the latest research on the mechanisms of angiogenesis in IH. We discuss the possible roles of three major factors, namely, estrogen, hypoxia, and inflammation, in the development of IH. Additionally, we summarize the key roles of tumor cell subpopulations, such as pericytes, in the proliferation and regression of IH considering evidence from the past few years, with an emphasis on the possible mechanisms of propranolol in the treatment of IH. Angiogenesis is an important event during the development of IH, and an in-depth understanding of the molecular mechanisms of angiogenesis will provide new insights into the biology and clinical treatment of IH.
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Hemangioma , Neovascularización Patológica , Humanos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Hemangioma/patología , Hemangioma/tratamiento farmacológico , Lactante , Propranolol/uso terapéutico , Propranolol/farmacología , Animales , Proliferación Celular/efectos de los fármacos , AngiogénesisRESUMEN
BACKGROUND: The progression of gallbladder cancer (GBC) is accompanied by abnormal fatty acid ß-oxidation (FAO) metabolism. Different types of lipids perform various biological functions. This study aimed to determine the role of acyl carnitines in the molecular mechanisms of GBC progression. METHODS: Distribution of lipids in GBC was described by LC-MS-based lipidomics. Cellular localization, expression level and full-length of lncBCL2L11 were detected using fluorescence in situ hybridization (FISH) assays, subcellular fractionation assay and 5' and 3' rapid amplification of the cDNA ends (RACE), respectively. In vitro and in vivo experiments were used to verify the biological function of lncBCL2L11 in GBC cells. Methylated RNA Immunoprecipitation (MeRIP) was performed to detect the methylation levels of lncBCL2L11. RNA pull-down assay and RNA immunoprecipitation (RIP) assay were used to identify lncBCL2L11 interacting proteins. Co-Immunoprecipitation (Co-IP) and Western blot assay were performed to validate the regulatory mechanism of lncBCL2L11 and THO complex. RESULTS: Acylcarnitines were significantly up-regulated in GBC tissues. High serum triglycerides correlated to decreased survival in GBC patients and promoted tumor migration. LncBCL2L11 was identified in the joint analysis of highly metastatic cells and RNA sequencing data. LncBCl2L11 prevented the binding of THOC6 and THOC5 and causes the degradation of THOC5, thus promoting the accumulation of acylcarnitines in GBC cells, leading to the malignant progression of cancer cells. In addition, highly expressed acylcarnitines stabilized the expression of lncBCL2L11 through N6-methyladenosine methylation (m6A), forming a positive feedback regulation in tumor dissemination. CONCLUSIONS: LncBCL2L11 is involved in gallbladder cancer metastasis through FAO metabolism. High lipid intake is associated with poor prognosis of GBC. Therefore, targeting lncBCL2L11 and its pathway-related proteins or reducing lipid intake may be significant for the treatment of GBC patients.
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Carnitina/análogos & derivados , Neoplasias de la Vesícula Biliar , Humanos , Neoplasias de la Vesícula Biliar/genética , Hibridación Fluorescente in Situ , ARN , Lípidos , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Proteínas Nucleares/metabolismo , Proteínas de Unión al ARN/genéticaRESUMEN
Gallbladder cancer (GBC) is a highly malignant and rapidly progressing tumor of the human biliary system, and there is an urgent need to develop new therapeutic targets and modalities. Non-POU domain-containing octamer-binding protein (NONO) is an RNA-binding protein involved in the regulation of transcription, mRNA splicing, and DNA repair. NONO expression is elevated in multiple tumors and can act as an oncogene to promote tumor progression. Here, we found that NONO was highly expressed in GBC and promoted tumor cells growth. The dysregulation of RNA splicing is a molecular feature of almost all tumor types. Accordingly, mRNA-seq and RIP-seq analysis showed that NONO promoted exon6 skipping in DLG1, forming two isomers (DLG1-FL and DLG1-S). Furthermore, lower Percent-Spliced-In (PSI) values of DLG1 were detected in tumor tissue relative to the paraneoplastic tissue, and were associated with poor patient prognosis. Moreover, DLG1-S and DLG1-FL act as tumor promoters and tumor suppressors, respectively, by regulating the YAP1/JUN pathway. N6-methyladenosine (m6A) is the most common and abundant RNA modification involved in alternative splicing processes. We identified an m6A reader, IGF2BP3, which synergizes with NONO to promote exon6 skipping in DLG1 in an m6A-dependent manner. Furthermore, IP/MS results showed that RBM14 was bound to NONO and interfered with NONO-mediated exon6 skipping of DLG1. In addition, IGF2BP3 disrupted the binding of RBM14 to NONO. Overall, our data elucidate the molecular mechanism by which NONO promotes DLG1 exon skipping, providing a basis for new therapeutic targets in GBC treatment.
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Proteínas de Unión al ADN , Neoplasias de la Vesícula Biliar , Humanos , Proteínas de Unión al ADN/genética , Neoplasias de la Vesícula Biliar/genética , Factores de Transcripción/genética , Empalme del ARN , Proliferación Celular , ARN Mensajero/genética , Línea Celular Tumoral , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Homólogo 1 de la Proteína Discs Large/genética , Homólogo 1 de la Proteína Discs Large/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismoRESUMEN
Recently, nanotechnology-based drug delivery platforms in treating pulmonary arterial hypertension (PAH) have gradually emerged. However, large mechanical stress and shear stress in blood vessels greatly affect the retention of nanopreparative materials at lesion sites, severely limiting nanotechnology-based drug delivery. Herein, a stimuli-responsive nanocraft is rationally designed by actively anchoring E-selectin overexpressed on pulmonary arterial endothelial cells (PAECs), under hypoxic conditions, allowing effective accumulation and retention of the drug at the lesion site. Briefly, a nitrobenzene group is incorporated into the framework of a nanocarrier, and then it is simultaneously linked with chitosan. Additionally, the surface of the nanocarrier with sialic acid (SA) and encapsulated the clinically used drug ambrisentan (Am), which enables the anchoring of E-selectin and subsequent drug delivery is modifed. This system facilitates intercellular transport to pulmonary artery smooth muscle cells (PASMCs) when targeting PAECs and specifically responds to a reductive hypoxic microenvironment with elevated nitroreductase in PASMCs. Moreover, compared with free Am, nanoencapsulation and SA-PEG2000-NH2 prolong the blood circulation time, achieving better therapeutic outcomes in preventing vascular remodeling and reversing systolic dysfunction. The originality and contribution of this work reveal the promising value of this pulmonary arterial anchoring stimuli-responsive nanocraft as a novel therapeutic strategy for satisfactory PAH treatment.
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Hipertensión Pulmonar , Miocitos del Músculo Liso , Arteria Pulmonar , Animales , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/metabolismo , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/citología , Arteria Pulmonar/efectos de los fármacos , Fenilpropionatos/química , Fenilpropionatos/farmacología , Quitosano/química , Vasoconstricción/efectos de los fármacos , Selectina E/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Nanopartículas/química , Hipoxia/metabolismo , Humanos , Masculino , Sistemas de Liberación de Medicamentos/métodos , Ratas , Ratas Sprague-Dawley , Ratones , PiridazinasRESUMEN
BACKGROUND: Gallbladder cancer (GBC) is the most aggressively malignant tumor in the bile duct system. The prognosis for patients with GBC is extremely poor. Ponicidin is a diterpenoid compound extracted and purified from the traditional Chinese herb Rabdosia rubescens, and showed promising anti-cancer effects in a variety of tumors. However, Ponicidin has not been investigated in GBC. METHODS: CCK-8, colony formation assay and EdU-488 DNA synthesis assay were performed to investigate the effect of Ponicidin on GBC cells proliferation. Cell invasion and migration assays and wound-healing assay were used to explore the effect of Ponicidin on invasion and migration ability of GBC cells. mRNA-seq was adopted to explore the underlying mechanisms. Western blot and immunohistochemical staining were conducted to detect the protein level. CHIP assay and dual-luciferase assay were used to validate binding motif. Nude mouse model of GBC was used to assess the anti-tumor effect and safety of Ponicidin. RESULTS: Ponicidin inhibited the proliferation and cell invasion and migration of GBC cells in vitro. Moreover, Ponicidin exerted anti-tumor effects by down-regulating the expression of MAGEB2. Mechanically, Ponicidin upregulated the FOXO4 expression and promoted it to accumulate in nucleus to inhibit the transcript of MAGEB2. Furthermore, Ponicidin suppressed tumor growth in the nude mouse model of GBC with excellent safety. CONCLUSION: Ponicidin may be a promising agent for the treatment of GBC effectively and safely.
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Diterpenos , Neoplasias de la Vesícula Biliar , Animales , Ratones , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/metabolismo , Neoplasias de la Vesícula Biliar/patología , Línea Celular Tumoral , Ratones Desnudos , Diterpenos/farmacología , Proliferación Celular , Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Proteínas de Ciclo Celular/metabolismo , Factores de Transcripción Forkhead/metabolismo , Antígenos de Neoplasias , Proteínas de Neoplasias/metabolismoRESUMEN
BACKGROUND: Acupotomy was used to treat tenosynovitis of hand flexor tendons (THFT) in China. But it's uncertain about the efficacy of acupotomy for THFT. We plan to evaluate the efficacy and safety about acupotomy therapy in the treatment of THFT through this review. METHODS: The protocol about this review was registered in PROSPERO (registration number: CRD42022330568). We searched 6 databases from their respective inception dates to January 11, 2022. Studies searched was screened by our reviewers, and then the raw data was filtered out. We used RevMan 5.3 software to perform statistical analysis. RESULTS: 11 studies involving 828 patients were shortlisted. The experimental group showed obvious advantages compared with the control group, such as effective rate (odds ratio [OR]â =â 6.77, 95% CI [confidence intervals]â =â [3.89, 11.77], Pâ <â .00001), cure rate (ORâ =â 3.32, 95% CIâ =â [1.81, 6.11], Pâ =â .0001) and Vas score (MDâ =â -1.21, 95% CIâ =â [-2.00, -0.42], Zâ =â 3.01, Pâ <â .003). CONCLUSIONS: According to the above results, Acupotomy is an effective and safe treatment for THFT. So it should be recommended for the treatment of THFT patients.
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Terapia por Acupuntura , Tenosinovitis , Humanos , Tenosinovitis/terapia , Terapia por Acupuntura/métodos , Proyectos de Investigación , Tendones , ChinaRESUMEN
With the development of intelligent sports in China and the rapid improvement of the strength of colleges and universities, the reform of traditional football players' header shooting training methods is becoming more and more urgent in order to solve some problems in the development of sports and speed up the intelligent training of Chinese football players. Based on this, this paper studies the biomechanical analysis and training method based on the integration of header strength data of football players. A dynamic header tracking model of football players based on a local search algorithm is designed. The data collection is realized from the aspects of athletes' header shooting training, skill improvement, physical consumption, and trajectory. The biological data of header shooting power is comprehensively analyzed and evaluated by using a local search algorithm. The results show that the training system based on a local search algorithm has the advantages of high feasibility, high data accuracy, and fast response speed. It can effectively conduct accurate guidance and improve the shooting accuracy according to the biological characteristics of header shooting intensity. This paper studies the biological analysis and training method of header strength of football players based on a local search algorithm. This has certain reference significance for accelerating the construction of intelligent training of Chinese football players.
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Fútbol Americano , China , Fútbol Americano/fisiología , Humanos , UniversidadesRESUMEN
China has experienced rapid industrial land growth over last three decades, which has brought about diverse social and environmental issues. Hence, it is extremely significant to monitor industrial land and intra-structure dynamics for industrial land management and industry transformation, but it is still a challenging task to effectively distinguish the internal structure of industrial land at a fine scale. In this study, we proposed a new framework for sensing the industrial land and intra-structure across the urban agglomeration around Hangzhou Bay (UAHB) during 2010-2015 through data on points of interest (POIs) and Google Earth (GE) images. The industrial intra-structure was identified via an analysis of industrial POI text information by employing natural language processing and four different machine learning algorithms, and the industrial parcels were photo-interpreted based on Google Earth. Moreover, the spatial pattern of the industrial land and intra-structure was characterized using kernel density estimation. The classification results showed that among the four models, the support vector machine (SVM) achieved the best predictive ability with an overall accuracy of 84.5%. It was found that the UAHB contains a huge amount of industrial land: the total area of industrial land rose from 112,766.9 ha in 2010 to 132,124.2 ha in 2015. Scores of industrial clusters have occurred in the urban-rural fringes and the coastal zone. The intra-structure was mostly traditional labor-intensive industry, and each city had formed own industrial characteristics. New industries such as the electronic information industry are highly encouraged to build in the core city of Hangzhou and the subcore city of Ningbo. Furthermore, the industrial renewal projects were also found particularly in the core area of each city in the UAHB. The integration of POIs and GE images enabled us to map industrial land use at high spatial resolution on a large scale. Our findings can provide a detailed industrial spatial layout and enable us to better understand the process of urban industrial dynamics, thus highlighting the implications for sustainable industrial land management and policy making at the urban-agglomeration level.
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Bahías , Tecnología de Sensores Remotos , Ciudades , China , Análisis Espacial , UrbanizaciónRESUMEN
BACKGROUND: Long noncoding RNAs (lncRNA) represent significant factors of the mammalian transcriptome that mediates varied biological and pathological processes. The liver is the most common site for gallbladder cancer (GBC) distant metastasis and contributes to the majority of GBC-related death. How lncRNA affects GBC metastasis is not completely understood. RESULTS: A novel lncRNA termed lncGALM (lncRNA in GBC associated with liver metastasis) was discovered to be highly expressed in cancer patients and xenografted tumors with liver metastasis. Elevated lncGALM in GBC patients also correlated to decreased survival. Invasion and migration of GBC cells were enhanced through lncGALM, both in vitro and in vivo. lncGALM functioned as sponges by competitively binding to and inactivating miR-200 family members, which increase epithelial-mesenchymal transition-associated transcription factor ZEB1 and ZEB2, leading to a fibroblastic phenotype and increased expression of N-cadherin. In addition, lncGALM bound to IL-1ß mRNA and stabilized the IL-1ß gene that mediates liver sinusoidal endothelial cell (LSECs) apoptosis. lncGALM-expressing LiM2-NOZ cells acquired a strong ability to migrate and adhere to LSECs, promoting LSECs apoptosis and therefore facilitating tumor cell extravasation and dissemination. CONCLUSIONS: lncGALM promotes GBC liver metastasis by facilitating GBC cell migration, invasion, liver arrest, and extravasation via the invasion-metastasis cascade. Targeting lncGALM may be protective against the development of liver metastasis in GBC patients.
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BACKGROUND: Benign prostatic hyperplasia (BPH) is a disease of the urinary system. It is common in middle-aged and elderly men. Moxibustion is widely used to manage BPH and the associated lower urinary tract symptoms, but there is still lack of systematic review of moxibusiton for BPH. So the aim of this review is to comprehensively evaluate the effectiveness and safety of moxibustion in the treatment of BPH. METHODS: The following 8 electronic databases including PubMed (1966-2020), EMbase (1980-2020), the Cochrane Library, Web of Science (1900-2020), China National Knowledge Infrastructure Database (1979-2020), WanFang Database (1998-2020), Chinese Scientific Journal Database (1989-2020), and Chinese Biomedical Literature Database (1979-2020) will be searched. No language restrictions will be used. Researchers will retrieve databases, identify trials, extract data, and evaluate the quality of eligible randomized controlled trials, independently. The outcomes will include: total effective rate, the American Urologic Association Symptom Score, International Prostate Symptom Score, urinary flow rate (measured in mL/s), changes in prostate size (measured in cc), quality of life, side effects and adverse events. The quality of methodology and evidence will be rated by using the Cochrane risk-of-bias assessment tool and grading of recommendations, assessment, development, and evaluation tool, respectively. Data synthesis will be presented by the manager of the Cochrane Collaboration's RevMan 5.3.0. RESULTS: We will show the results of this study in a peer-reviewed journal. CONCLUSIONS: The findings will provide credible clinical evidence of moxibustion treatment for BPH. PROSPERO REGISTRATION NUMBER: CRD42020190630.
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Moxibustión , Hiperplasia Prostática/terapia , Humanos , Masculino , Metaanálisis como Asunto , Revisiones Sistemáticas como AsuntoRESUMEN
BACKGROUNDS: Long non-coding RNAs (lncRNAs) are essential factors that regulate tumor development and metastasis via diverse molecular mechanisms in a broad type of cancers. However, the pathological roles of lncRNAs in gallbladder carcinoma (GBC) remain largely unknown. Here we discovered a novel lncRNA termed lncRNA Highly expressed in GBC (lncRNA-HGBC) which was upregulated in GBC tissue and aimed to investigate its role and regulatory mechanism in the development and progression of GBC. METHODS: The expression level of lncRNA-HGBC in GBC tissue and different cell lines was determined by quantitative real-time PCR. The full length of lncRNA-HGBC was obtained by 5' and 3' rapid amplification of the cDNA ends (RACE). Cellular localization of lncRNA-HGBC was detected by fluorescence in situ hybridization (FISH) assays and subcellular fractionation assay. In vitro and in vivo assays were preformed to explore the biological effects of lncRNA-HGBC in GBC cells. RNA pull-down assay, mass spectrometry, and RNA immunoprecipitation (RIP) assay were used to identify lncRNA-HGBC-interacting proteins. Dual luciferase reporter assays, AGO2-RIP, and MS2-RIP assays were performed to verify the interaction between lncRNA-HGBC and miR-502-3p. RESULTS: We found that lncRNA-HGBC was upregulated in GBC and its upregulation could predict poor survival. Overexpression or knockdown of lncRNA-HGBC in GBC cell lines resulted in increased or decreased, respectively, cell proliferation and invasion in vitro and in xenografted tumors. LncRNA-HGBC specifically bound to RNA binding protein Hu Antigen R (HuR) that in turn stabilized lncRNA-HGBC. LncRNA-HGBC functioned as a competitive endogenous RNA to bind to miR-502-3p that inhibits target gene SET. Overexpression, knockdown or mutation of lncRNA-HGBC altered the inhibitory effects of miR-502-3p on SET expression and downstream activation of AKT. Clinically, lncRNA-HGBC expression was negatively correlated with miR-502-3p, but positively correlated with SET and HuR in GBC tissue. CONCLUSIONS: Our study demonstrates that lncRNA-HGBC promotes GBC metastasis via activation of the miR-502-3p-SET-AKT cascade, pointing to lncRNA-HGBC as a new prognostic predictor and a therapeutic target.
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Proteínas de Unión al ADN/genética , Proteína 1 Similar a ELAV/genética , Neoplasias de la Vesícula Biliar/genética , Regulación Neoplásica de la Expresión Génica , Chaperonas de Histonas/genética , MicroARNs/genética , Proteínas Proto-Oncogénicas c-akt/genética , ARN Largo no Codificante/genética , Adulto , Anciano , Biomarcadores de Tumor , Línea Celular Tumoral , Proliferación Celular , Proteínas de Unión al ADN/metabolismo , Progresión de la Enfermedad , Femenino , Neoplasias de la Vesícula Biliar/metabolismo , Neoplasias de la Vesícula Biliar/patología , Chaperonas de Histonas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARNRESUMEN
In the original publication of this article [1], there are mistakes in Fig. 3A and Fig. 3D.
RESUMEN
NOP2/Sun domain family, member 2 (NSUN2) is a nuclear RNA methyl-transferase catalyzing 5-methylcytosine formation. Evidence shows that NSUN2 is correlated with cell unlimited proliferation. However, its functional role in gallbladder carcinoma (GBC), which is the most common biliary tract malignancy and has a poor prognosis, remains to be determined. Here we found that NSUN2 was highly expressed in GBC tissues as well as cell lines. NSUN2 silencing repressed GBC cell proliferation and tumorigenesis both in vitro and in vivo. Conversely, upregulation of NSUN2 enhanced GBC cell growth and colony formation. We further discovered that RPL6 was a closely interacting partner with NSUN2. Silencing RPL6 resulted in insufficient NSUN2 translational level and accumulative NSUN2 transcriptional level. Exogenous expression of NSUN2 partially rescued the effect of RPL6 in gallbladder cancer progression. Taken together, our data provided novel mechanic insights into the function of NSUN2 in GBC, thus pointing to NSUN2 as a potential and effective therapeutic approach to GBC treatment.
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Carcinoma/metabolismo , Neoplasias de la Vesícula Biliar/metabolismo , Metiltransferasas/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Ribosómicas/metabolismo , Animales , Carcinoma/patología , Carcinoma/terapia , Línea Celular Tumoral , Proliferación Celular , Colecistitis/metabolismo , Progresión de la Enfermedad , Neoplasias de la Vesícula Biliar/patología , Neoplasias de la Vesícula Biliar/terapia , Humanos , Metiltransferasas/antagonistas & inhibidores , Ratones , Ratones Desnudos , Ensayo de Tumor de Célula Madre , Regulación hacia ArribaRESUMEN
OBJECTIVES: Patients with gallbladder carcinoma (GBC) lack effective treatment methods largely due to the inadequacy of both molecular characterisation and potential therapeutic targets. We previously uncovered a spectrum of genomic alterations and identified recurrent mutations in the ErbB pathway in GBC. Here, we aimed to study recurrent mutations of genes and pathways in a larger cohort of patients with GBC and investigate the potential mechanisms and clinical significance of these mutations. DESIGN: We performed whole-exome sequencing (WES) in 157 patients with GBC. Functional experiments were applied in GBC cell lines to explore the oncogenic roles of ERBB2/ERBB3 hotspot mutations, their correlation with PD-L1 expression and the underlying mechanisms. ERBB inhibitors and a PD-L1 blocker were used to evaluate the anticancer activities in co-culture systems in vitro and in vivo. RESULTS: WES identified ERBB2 and ERBB3 mutations at a frequency of 7%-8% in the expanded cohort, and patients with ERBB2/ERBB3 mutations exhibited poorer prognoses. A set of in vitro and in vivo experiments revealed increased proliferation/migration on ERBB2/ERBB3 mutation. Ectopic expression of ERBB2/ERBB3 mutants upregulated PD-L1 expression in GBC cells, effectively suppressed normal T-cell-mediated cytotoxicity in vitro through activation of the PI3K/Akt signalling pathway and contributed to the growth and progression of GBC in vivo. Treatment with an ERBB2/ERBB3 inhibitor or a PD-L1 monoclonal antibody reversed these immunosuppressive effects, and combined therapy revealed promising therapeutic activities. CONCLUSIONS: ERBB2/ERBB3 mutations may serve as useful biomarkers in identifying patients who are sensitive to ERBB2/ERBB3 inhibitors and PD-L1 monoclonal antibody treatment. TRIAL REGISTRATION NUMBER: NCT02442414;Pre-results.
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Antígeno B7-H1/genética , Secuenciación del Exoma , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/inmunología , Receptor ErbB-2/genética , Anticuerpos Monoclonales/farmacología , Antígeno B7-H1/efectos de los fármacos , Línea Celular Tumoral , Análisis Mutacional de ADN , Femenino , Genómica , Humanos , Masculino , Terapia Molecular Dirigida , Medición de Riesgo , Sensibilidad y Especificidad , Transducción de Señal/efectos de los fármacosRESUMEN
Karyopherin alpha 2 (KPNA2) is a nuclear import factor that is elevated in multiple cancers. However, its molecular regulation at the transcriptional levels is poorly understood. Here we found that KPNA2 was significantly upregulated in gallbladder cancer (GBC), and the increased levels were correlated with short survival of patients. Gene knocking down of KPNA2 inhibited tumor cell proliferation and migration in vitro as well as xenografted tumor development in vivo. A typical transcription factor E2F1 associated with its DNA-binding partner DP1 bond to the promoter region of KPNA2 and induced KPNA2 expression. In contrast, an atypical transcription factor E2F7 competed against DP1 and blocked E2F1-induced KPNA2 gene activation. Mutation of the dimerization residues of E2F7 or DNA-binding domain of E2F1 abolished the suppressive effects of E2F7 on KPNA2 gene expression. In addition, KPNA2 mediated nuclear localization of E2F1 and E2F7, where they in turn controlled KPNA2 expression. Taken together, our data provided mechanistic insights into divergently transcriptional regulation of KPNA2, thus pointing to KPNA2 as a potential target for cancer therapy.
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Factor de Transcripción E2F1/genética , Factor de Transcripción E2F7/genética , Neoplasias de la Vesícula Biliar/genética , alfa Carioferinas/genética , Adulto , Anciano , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Proteínas de Unión al ADN/genética , Femenino , Neoplasias de la Vesícula Biliar/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Persona de Mediana Edad , Estadificación de Neoplasias , Factor de Transcripción DP1/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Hesperidin is a vitamin P flavonoid compound primarily present in citrus fruits, which possesses an anti-inflammatory effect. The functional role of hesperidin in interleukin (IL)-1ß-stimulated human osteoarthritis (OA) chondrocytes is still unknown. In the present study, anti-inflammatory effects of hesperidin in IL-1ß-stimulated chondrocytes were investigated. The results demonstrated that hesperidin treatment markedly decreased nitric oxide and prostaglandin E2 production and markedly downregulated inducible nitric oxide synthase and cyclooxygenase-2 expression in IL-1ß-stimulated OA chondrocytes. In addition, hesperidin markedly reduced IL-1ß-induced matrix metalloproteinase (MMP)-3 and MMP-13 expression in human OA chondrocytes. Furthermore, hesperidin markedly decreased the activation of nuclear factor (NF)-κB in human OA chondrocytes. In conclusion, it was revealed for the first time that hesperidin inhibited inflammatory responses in IL-1ß-stimulated human chondrocytes, potentially through inhibiting the activation of the NF-κB signaling pathway. These data suggest that hesperidin may be a potential agent for the treatment of OA.