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1.
Histol Histopathol ; : 18512, 2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36093844

RESUMO

Gastric adenocarcinoma (GAC) caused by malignant transformation of gastric adenocytes is a malignancy with high incidence. MiR-195-5p modulates a variety of cancers. One of its target genes, orthodenticle homeobox 1 (OTX1), is believed to be a key modulator of tumor progression. We aim to analyze the mechanism of miR-195-5p and OTX1 in GAC. MiR-195-5p and OTX1 mRNA levels in GAC cells were tested via qRT-PCR. OTX1 protein and EMT-related protein levels were examined through western blot. Several cell functional assays were designed to measure changes in cell malignant behaviors. Dual luciferase assay verified the targeting relation of miR-195-5p and OTX1. These experimental results showed significantly low miR-195-5p expression and significantly high OTX1 expression in GAC cells. Enforced miR-195-5p level repressed cell malignant progression and accelerated cell apoptosis in GAC. Increased OTX1 weakened the above-mentioned effect caused by overexpressing miR-195-5p. Thus, miR-195-5p restrained migration, proliferation, invasion and epithelial-mesenchymal transition process of GAC cells, and promoted cell apoptosis through regulating OTX1. A new insight is provided for searching for biomarkers or therapeutic targets of GAC.

2.
Clin Pharmacol Ther ; 2022 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-36151921

RESUMO

Access to anticancer drugs has been a critical health issue in China for many years. We retrospectively analyzed the novel anticancer drugs approved in the United States (The U.S.) between 2010-2021 to assess the evolving landscape of the drug lags in China by taking Japan and the European Union (EU) as comparisons. The absolute and relative lags of drug initial approval (DIA) and indication approval were calculated between China (or Japan/EU) and the U.S. Based on the U.S. approval date of novel agents, the duration was divided into 2010-2015 and 2016-2021. Overall, 123 (244 indications) new molecular entities (NMEs) approved in the U.S. were included, of which 58 (94 indications), 72 (128 indications) and 99 (170 indications) NMEs were also approved in China, Japan and the EU, respectively. The absolute lags of DIA and indications approval in China improved dramatically in 2016-2021 compared to 2010-2015. Similarly, the relative DIA and indication approval lags in China decreased significantly in 2016-2021. The median review lags for DIA of China in 2016-2021 were comparable to Japan but dramatically lower than that of the EU. Nevertheless, China had significantly longer median submission lags for DIA (28 months) in 2016-2021 than that of Japan (6 months) and the EU (1 month). Although the absolute and relative lags of anticancer drugs in China had been initially addressed, 53% of NMEs and 61% of indications were still not approved for cancers in China compared with the U.S. Therefore, China should adopt steps to further reduce drug lags.

3.
Artigo em Inglês | MEDLINE | ID: mdl-36124946

RESUMO

OBJECTIVE: To explore whether the variants in non-MHC proteasome gene is associated with ankylosing spondylitis and explain the role of the variant in the disease. METHODS: Case-control analysis to identify ankylosing spondylitis predisposition genes; dual-luciferase reporter assay, immunoblot analysis and osteoclastogenesis assays to detect the function of the positive variant. Affected individuals was diagnosed according to the modified New York Criteria by at least two experienced rheumatologists, and rechecked by another rheumatologist. RESULTS: The study included 1037 AS patients and 1014 no rheumatic and arthritis disease controls. The main age of AS onset is between 16 and 35 years old. HLA-B27-positive subjects comprised 90.0% of patients. A nonsynonymous SNP rs12717 in proteasome gene PSMB1 significantly associated with ankylosing spondylitis. Individuals with CC genotype had a higher onset risk compared with those with GG/GC genotypes (OR = 1.89, p= 0.0047). We also discovered that PSMB1 regulates the receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL) signalling pathway and the disease-associated variant PSMB1-Pro11 significantly inhibits RANKL-induced NF-κB pathway in osteoclast differentiation via the degradation of IKK-ß compared with PSMB1-Ala11. RANKL induced osteoclast differentiation was significantly lower in primary monocyte osteoclast precursor from individuals with genotype PSMB131C/31C compared with individuals with genotype PSMB131G/31G. CONCLUSIONS: These results reveal a novel understanding of the bone formation and reabsorbing imbalance in AS. The new bone formation phenotype can be attributed to the inhibition of osteoclast differentiation by a more functional PSMB1 gene.

5.
Drug Discov Today ; : 103370, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36154876

RESUMO

The implementation of China's breakthrough therapy designation (BTD) program in 2020 to accelerate drug development for serious or life-threatening diseases has attracted widespread attention. Here, we review the characteristics of BTD and its implementation in China. Overall, 78 drugs with 82 BTDs were collected from the program's inception to April 2022. The time to obtain BTD for imported new drugs was significantly faster than for domestic ones. The BTDs granted for domestic new drugs were highly concentrated in oncology. The BTD drugs can reduce clinical trial and review times compared with non-BTD drugs. The implementation of BTD is expected to expedite the development of new drugs to address unmet clinical needs in China.

6.
Comput Intell Neurosci ; 2022: 9640673, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36045967

RESUMO

The improvement of small target detection and obscuration handling is the key problem to be solved in the object detection task. In the field operation of chemical plant, due to the occlusion of construction workers and the long distance of surveillance shooting, it often leads to the phenomenon of missed detection. Most of the existing work uses multiple feature fusion strategies to extract different levels of features and then aggregate them into global features, which does not utilize local features and makes it difficult to improve the performance of small target detection. To address this issue, this paper introduces Point Transformer, a transformer encoder, as the core backbone of the object detection framework that first uses a priori information of human skeletal points to obtain local features and then uses both self-attention and cross-attention mechanisms to reconstruct the local features corresponding to each key point. In addition, since the target to be detected is highly correlated with the position of human skeletal points, to further boost Point Transformer's performance, a learnable positional encoding method is proposed by us to highlight the position characteristics of each skeletal point. The proposed model is evaluated on the dataset of field operation in a chemical plant. The results are significantly better than the classical algorithms. It also outperforms state-of-the-art by 12 percent of map points in the small target detection task.


Assuntos
Algoritmos , Humanos
8.
Endocrine ; 2022 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-35962894

RESUMO

BACKGROUND: Graves' disease (GD) is an autoimmune disease, the incidence of which is increasing yearly. GD requires long-life therapy. Therefore, the potential immune-related biomarkers of GD need to be studied. METHOD: In our study, differentially expressed genes (DEGs) were derived from the online Gene Expression Omnibus (GEO) microarray expression dataset GSE71956. Protein‒protein interaction (PPI) network analyses were used to identify hub genes, which were validated by qPCR. GSEA was used to screen potential pathways and related immune cells. Next, CIBERSORT analysis was used to further explore the immune subtype distribution pattern among hub genes. ROC curves were used to analyze the specificity and sensitivity of hub genes. RESULT: 44 DEGs were screened from the GEO dataset. Two hub genes, EEF1A1 and EIF4B, were obtained from the PPI network and validated by qPCR (p < 0.05). GSEA was conducted to identify potential pathways and immune cells related to these the two hub genes. Immune cell subtype analysis revealed that hub genes had extensive associations with many different types of immune cells, particularly resting memory CD4+ T cells. AUCs of ROC analysis were 0.687 and 0.733 for EEF1A1 and EIF4B, respectively. CONCLUSION: Our study revealed two hub genes, EEF1A1 and EIF4B, that are associated with resting memory CD4+ T cells and potential immune-related molecular biomarkers and therapeutic targets of GD.

10.
Mol Pharm ; 19(9): 3350-3357, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-35985030

RESUMO

X-ray photoelectron spectroscopy has been used to measure the surface concentration and the surface enrichment kinetics of a polymer in a glass-forming molecular liquid. As a model, the bulk-miscible system of maltitol-polyvinylpyrrolidone (PVP) was studied. The PVP concentration is significantly higher at the liquid/vapor interface than in the bulk by up to a factor of 170, and the effect increases with its molecular weight. At a freshly created liquid/vapor interface, the concentration of PVP gradually increases from the bulk value at a rate controlled by bulk diffusion. The polymer diffusion coefficient obtained from the kinetics of surface enrichment agrees with that calculated from viscosity and the Stokes-Einstein equation. Our finding allows prediction of the rate at which the surface composition equilibrates in an amorphous material after milling, fracture, and a change in ambient temperature.


Assuntos
Polímeros , Povidona , Vidro , Cinética , Polímeros/química , Povidona/química , Solubilidade
12.
Eur J Pharmacol ; 931: 175184, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35964659

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia with limited therapeutic options. Eucalyptol, a terpenoid oxide isolated from eucalyptus species, reportedly exhibits various biological activities such as anti-inflammatory and antioxidant effects. In the present study, we aimed to determine whether eucalyptol could alleviate bleomycin (BLM)-induced pulmonary fibrosis and inhibit interleukin (IL)-13-induced M2 macrophage polarization. Upon treatment with eucalyptol, BLM-induced pulmonary fibrosis and lung inflammation were significantly reduced. The pulmonary neutrophil accumulation and pulmonary permeability were inhibited and the expression of hydroxyproline, alpha-smooth muscle actin, and fibronectin was significantly down-regulated. Eucalyptol also markedly inhibited the expression of arginase-1, Ym-1, IL-13, and transforming growth factor (TGF)-ß1, reduced the production of IL-13, IL-6, tumor necrosis factor (TNF)-α, and attenuated the activity of TGF-ß1 in bronchoalveolar lavage fluid (BALF). Furthermore, the in vitro assay revealed that eucalyptol disturbed M2 macrophage polarization and reduced the macrophage-mediated secretion of the profibrotic factor TGF-ß1. Eucalyptol inhibited the nuclear location of signal transducer and activator of transcription 6 (STAT6) and the phosphorylation of STAT6 and p38 mitogen-activated protein kinase (p38 MAPK), and reduced the expression of their downstream transcription factors, krupple-like factor 4 (KLF4) and peroxisome proliferator-activated receptor gamma (PPAR-γ). These findings indicated that eucalyptol alleviates BLM-induced pulmonary fibrosis by regulating M2 macrophage polarization, which, in turn, inhibits the activation of signaling molecules (e.g., STAT6 and p38 MAPK) and the expression of transcription factors (e.g., KLF4 and PPAR-γ). Thus, eucalyptol might be a potential therapeutic agent for IPF.


Assuntos
Bleomicina , Fibrose Pulmonar , Bleomicina/efeitos adversos , Eucaliptol/farmacologia , Eucaliptol/uso terapêutico , Humanos , Interleucina-13/metabolismo , Pulmão/patologia , Macrófagos/metabolismo , PPAR gama/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/prevenção & controle , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Front Pharmacol ; 13: 939039, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35846991

RESUMO

Very few anti-Alzheimer's disease (AD) drugs are clinically available at present due to the complex mechanism of Alzheimer's disease. For the purpose of discovering potential anti-AD drugs in bisbenzylisoquinoline alkaloids, the anti-AD function and the mechanism of the function of berbamine hydrochloride (BBMH) were studied. Three kinds of AD model mice, double transgenic APP/PS1 AD mice, Gal-Alu AD mice induced by the intraperitoneal injection of d-galactose combined with the intragastric administration of aluminum trichloride, and Alu AD-like mice induced by stereotactic brain injection of aluminum trichloride, were administered with BBMH for 40 days at a dosage of 280 mg/kg/d. The effects of BBMH on the learning and memory behavior of the AD mice were studied through the Morris water maze experiment, and the influences of BBMH on the pathological features of AD, including the deposition of Aß, the lesions of pyramidal cells (neurons), and the formation of neurofibrillary tangles, were studied by the immunohistochemical staining, hematoxylin-eosin staining, and silver staining of the brain tissues of the mice. The water maze experiment showed that BBMH could significantly improve the learning and memory abilities of three kinds of treated mice. Immunohistochemical staining showed that BBMH could significantly reduce the deposition of Aß in the brain tissues of treated mice. Hematoxylin-eosin staining showed that BBMH could significantly alleviate the lesions of pyramidal cells in the hippocampal tissue of the mice. Silver staining showed that BBMH could significantly reduce the formation of neurofibrillary tangles in the hippocampal tissue of the mice. These results indicated that BBMH has significant anti-AD effects and the potential as an anti-AD drug. Western blot analysis of the brain tissue of the mice showed that the expression level of calpain, a Ca2+-dependent proteolytic enzyme, was significantly inhibited and the expression level of SelK, a selenoprotein mainly expressed in immune cells, was significantly increased. It is speculated that the anti-AD effect of BBMH is related to the improvement of the phagocytosis of microglial cells in brain tissues and macrophages migrated into the brain as well as the regulation of calcium homeostasis and calcium-dependent proteases in the brain tissues of the mice.

14.
J Control Release ; 349: 876-889, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35907592

RESUMO

NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme significantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) tumors compared to the associated normal tissues. NQO1 bioactivatable drugs, such as ß-lapachone (ß-lap), can be catalyzed to generate reactive oxygen species (ROS) for direct tumor killing. However, the extremely narrow therapeutic window caused by methemoglobinemia and hemolytic anemia severely restricts its further clinical translation despite considerable efforts in the past 20 years. Previously, we demonstrated that albumin could be utilized to deliver cytotoxic drugs selectively into KRAS-mutant PDAC with a much expanded therapeutic window due to KRAS-enhanced macropinocytosis and reduced neonatal Fc receptor (FcRn) expression in PDAC. Herein, we analyzed the expression patterns of albumin and FcRn across major organs in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mice. The tumors were the predominant tissues with both elevated albumin and reduced FcRn expression, thus making them an ideal target for albumin-based drug delivery. Quantitative proteomics analysis of tissue samples from 5 human PDAC patients further confirmed the elevated albumin/FcRn ratio. Given such a compelling biological rationale, we designed a nanoparticle albumin-bound prodrug of ß-lap, nab-(pro-ß-lap), to achieve PDAC targeted delivery and expand the therapeutic window of ß-lap. We found that nab-(pro-ß-lap) uptake was profoundly enhanced by KRAS mutation. Compared to the solution formulation of the parent drug ß-lap, nab-(pro-ß-lap) showed enhanced safety due to much lower rates of methemoglobinemia and hemolytic anemia, which was confirmed both in vitro and in vivo. Furthermore, nab-(pro-ß-lap) significantly inhibited tumor growth in subcutaneously implanted KPC xenografts and enhanced the pharmacodynamic endpoints (e.g., PARP1 hyperactivation, γ-H2AX). Thus, nab-(pro-ß-lap), with improved safety and antitumor efficacy, offers a drug delivery strategy with translational viability for ß-lap in pancreatic cancer therapy.


Assuntos
Carcinoma Ductal Pancreático , Metemoglobinemia , Naftoquinonas , Neoplasias Pancreáticas , Pró-Fármacos , Albuminas/metabolismo , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Metemoglobinemia/tratamento farmacológico , Camundongos , NAD/metabolismo , NAD/uso terapêutico , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Quinonas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo
15.
Hortic Res ; 9: uhac109, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35821703

RESUMO

G proteins function directly in cold tolerance of plants. However, the framework of the Gα subunit in regulating cold tolerance remains to be explored. Here, we used protein interaction techniques to elucidate cold-related pathways regulated by CsGPA1. Suppression of CsGPA1 decreased the cold tolerance of cucumber. Further protein interaction experiments showed that CsGPA1 interacted with Csa_4G663630.1 located in the cell membrane and nucleus and with CsCOR413PM2 located in the cell membrane. Csa_4G663630.1 was named CsCDL1 due to its 71% protein sequence similarity to AtCDL1, a positive brassinolide signal gene. Suppression of CsGPA1 decreased the expression of most of brassinolide-related genes (including CsCDL1) under cold stress. Principal component and linear regression analyses showed that expressions of CsGPA1 and brassinolide-related genes were positively correlated. Suppression of CsCOR413PM2 also decreased cold tolerance of cucumber. The expression and protein content of CsCOR413PM2 and CsGPA1 in CsGPA1-RNAi and CsCOR413PM2-RNAi lines were determined under cold tolerance. Only CsGPA1 silencing affected the expression and protein content of CsCOR413PM2 during cold stress. Moreover, suppression of CsGPA1 or CsCOR413PM2 decreased Ca 2+ influx at low temperature and then decreased the expression of CsICE-CsCBF. These results indicated that the CsGPA1-CsCOR413PM2-Ca2+ axis regulated the expression of CsICE-CsCBF during cold stress. In conclusion, Our results provide the first framework of CsGPA1 in regulating cold tolerance of cucumber, laying the foundation for further mechanistic studies of cold tolerance for Gα in cucumber.

16.
Front Mol Biosci ; 9: 936070, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35832738

RESUMO

Primary cilia play counterregulatory roles in cystogenesis-they inhibit cyst formation in the normal renal tubule but promote cyst growth when the function of polycystins is impaired. Key upstream cilia-specific signals and components involved in driving cystogenesis have remained elusive. Recent studies of the tubby family protein, Tubby-like protein 3 (TULP3), have provided new insights into the cilia-localized mechanisms that determine cyst growth. TULP3 is a key adapter of the intraflagellar transport complex A (IFT-A) in the trafficking of multiple proteins specifically into the ciliary membrane. Loss of TULP3 results in the selective exclusion of its cargoes from cilia without affecting their extraciliary pools and without disrupting cilia or IFT-A complex integrity. Epistasis analyses have indicated that TULP3 inhibits cystogenesis independently of the polycystins during kidney development but promotes cystogenesis in adults when polycystins are lacking. In this review, we discuss the current model of the cilia-dependent cyst activation (CDCA) mechanism in autosomal dominant polycystic kidney disease (ADPKD) and consider the possible roles of ciliary and extraciliary polycystins in regulating CDCA. We then describe the limitations of this model in not fully accounting for how cilia single knockouts cause significant cystic changes either in the presence or absence of polycystins. Based on available data from TULP3/IFT-A-mediated differential regulation of cystogenesis in kidneys with deletion of polycystins either during development or in adulthood, we hypothesize the existence of cilia-localized components of CDCA (cCDCA) and cilia-localized cyst inhibition (CLCI) signals. We develop the criteria for cCDCA/CLCI signals and discuss potential TULP3 cargoes as possible cilia-localized components that determine cystogenesis in kidneys during development and in adult mice.

17.
Mol Pharm ; 2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35759395

RESUMO

Drug-polymer interactions are of great importance in amorphous solid dispersion (ASD) formulation for both dissolution performance and physical stability considerations. In this work, three felodipine ASD systems with drug loading ranging from 5 to 20% were prepared using PVP, PVP-VA, or HPMC-AS as the polymer matrix. The amorphization and homogeneity were confirmed by differential scanning calorimetry and powder X-ray diffraction. The intrinsic dissolution behavior of these ASDs was studied in 0.05 M HCl and phosphate-buffered saline (PBS) (pH 6.5). In 0.05 M HCl, PVP-VA ASDs with low drug loading (<15%) showed rapid dissolution accompanied with nano-species generation, while in the PVP system, rapid dissolution and nano-species generation were observed only when drug loading was less than 10%, and HPMC-AS ASDs always released slowly with no nano-species formation. In PBS, PVP-VA ASDs with drug loading less than 10% showed rapid dissolution accompanied with nano-species generation, while for PVP ASDs, rapid dissolution and nano-species generation were observed only when drug loading was 5%. However, 20% drug loading HPMC-AS ASDs exhibited rapid dissolution of felodipine and nano-species generation. When the drug loading was above the transition point of PVP-VA ASDs and PVP ASDs, the release rate was significantly lowered, and no nano-species was generated. To understand this phenomenon, drug-polymer interactions were studied using the melting point depression method and the Flory-Huggins model fitting. The Flory-Huggins interaction parameters (χ) for felodipine/HPMC-AS, felodipine/PVP, and felodipine/PVP-VA were determined to be 0.62 ± 0.07, -0.55 ± 0.20, and -1.02 ± 0.21, respectively, indicating the existence of the strongest attractive molecular interaction between felodipine and PVP-VA, followed by felodipine/PVP, but not in felodipine/HPMC-AS. Furthermore, dynamic vapor sorption further revealed that the molecular interactions between felodipine and PVP or PVP-VA were resistant to water. We concluded that water-resistant drug-polymer interactions in felodipine/polymer systems were responsible for the formation of nano-species, which further facilitated the rapid initial drug dissolution.

18.
Artigo em Inglês | MEDLINE | ID: mdl-35737613

RESUMO

Decomposing data matrix into low-rank plus additive matrices is a commonly used strategy in pattern recognition and machine learning. This article mainly studies the alternating direction method of multiplier (ADMM) with two dual variables, which is used to optimize the generalized nonconvex nonsmooth low-rank matrix recovery problems. Furthermore, the minimization framework with a feasible optimization procedure is designed along with the theoretical analysis, where the variable sequences generated by the proposed ADMM can be proved to be bounded. Most importantly, it can be concluded from the Bolzano-Weierstrass theorem that there must exist a subsequence converging to a critical point, which satisfies the Karush-Kuhn-Tucher (KKT) conditions. Meanwhile, we further ensure the local and global convergence properties of the generated sequence relying on constructing the potential objective function Particularly, the detailed convergence analysis would be regarded as one of the core contributions besides the algorithm designs and the model generality. Finally, the numerical simulations and the real-world applications are both provided to verify the consistence of the theoretical results, and we also validate the superiority in performance over several mostly related solvers to the tasks of image inpainting and subspace clustering.

19.
FEBS Open Bio ; 12(8): 1542-1557, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35674216

RESUMO

Glucocorticoid-induced TNF receptor-related (GITR) can act as a co-stimulatory receptor, representing a potential target for safely enhancing immunotherapy efficacy. GITR is triggered by a GITR ligand or an agonist antibody and activates CD8+ and CD4+ effector T cells, reducing tumor-infiltrating Treg numbers and resulting in activation of immune responses and tumor cell destruction by effector T cells. GITR is an attractive target for immunotherapy, especially in combination therapy with immune checkpoint inhibitors, as is being explored in clinical trials. Using H2L2 transgenic mice encoding the human immunoglobulin variable region and hybridoma technology, we generated a panel of fully human antibodies that showed excellent specific affinity and strong activation of human T cells. After conversion to fully human antibodies and engineering modification, we obtained an anti-GITR antibody hab019e2 with enhanced antitumor activity in a B-hGITR MC38 mouse model compared to Tab9H6V3, an anti-GITR antibody that activates T cells and inhibits Treg suppression from XenoMouse. As a fully human antibody with its posttranslational modification hot spot removed, the hab019e2 antibody exerted more potent therapeutic effects, and may have potential as a novel and developable antibody targeting GITR for follow-up drug studies.


Assuntos
Glucocorticoides , Receptores do Fator de Necrose Tumoral , Animais , Anticorpos , Linhagem Celular Tumoral , Proteína Relacionada a TNFR Induzida por Glucocorticoide/agonistas , Humanos , Imunoterapia/métodos , Camundongos , Receptores do Fator de Necrose Tumoral/agonistas
20.
Clin Exp Metastasis ; 39(4): 691-710, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35661947

RESUMO

Plexin-domain containing 2 (PLXDC2) has been reported as an oncoprotein in several human malignancies. However, its expression and roles in gastric cancer remain largely unclear. In this study, we found that PLXDC2 was highly expressed in gastric cancer tissues, and the expression levels were positively correlated with clinicopathological features, but negatively with the patients' outcome. Cox regression analysis identified PLXDC2 as an independent prognostic indicator for the patients. Knockdown of PLXDC2 markedly suppressed the in vitro invasion and in vivo metastasis of gastric cancer cells, while overexpression of PLXDC2 resulted in opposite effects. Mechanistically, PLXDC2 enhanced the level of phosphorylated Cortactin (p-Cortactin) by physically interacting with protein tyrosine phosphatase 1B (PTP1B), an important dephosphorylase, to prevent its dephosphorylating of p-Cortactin, thereby promoting the formation of invadopodia. Collectively, our results indicate that PLXDC2 contributes to the invasion and metastasis of gastric cancer by inhibiting PTP1B to facilitate the invadopodium formation, and may serve as a potential prognostic biomarker and a therapeutic target for this disease.


Assuntos
Podossomos , Neoplasias Gástricas , Linhagem Celular Tumoral , Cortactina/genética , Cortactina/metabolismo , Humanos , Invasividade Neoplásica , Monoéster Fosfórico Hidrolases/metabolismo , Podossomos/metabolismo , Podossomos/patologia , Receptores de Superfície Celular , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
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