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BACKGROUND: Recent advancements in biliary tract cancer (BTC) treatment have expanded beyond surgery to include adjuvant therapy, yet the prognosis remains poor. Identifying prognostic biomarkers could enhance the assessment of patients who have undergone radical resection for BTC. AIM: To determine transmembrane serine protease 4 (TMPRSS4) utility as a prognostic biomarker of radical resection for BTC. METHODS: Medical records of patients who underwent radical resection for BTC, excluding intrahepatic cholangiocarcinoma, were retrospectively reviewed. The associations between TMPRSS4 expression and clinicopathological factors, overall survival, and recurrence-free survival were analyzed. RESULTS: Among the 85 patients undergoing radical resection for BTC, 46 (54%) were TMPRSS4-positive. The TMPRSS4-positive group exhibited significantly higher preoperative carbohydrate antigen 19-9 (CA19-9) values and greater lymphatic invasion than the TMPRSS4-negative group (P = 0.019 and 0.039, respectively). Postoperative overall survival and recurrence-free survival were significantly worse in the TMPRSS4-positive group (median survival time: 25.3 months vs not reached, P < 0.001; median survival time: 28.7 months vs not reached, P = 0.043, respectively). Multivariate overall survival analysis indicated TMPRSS4 positivity, pT3/T4, and resection status R1 were independently associated with poor prognosis (P = 0.032, 0.035 and 0.030, respectively). TMPRSS4 positivity correlated with preoperative CA19-9 values ≥ 37 U/mL and pathological tumor size ≥ 30 mm (P = 0.016 and 0.038, respectively). CONCLUSION: TMPRSS4 is a potential prognostic biomarker of radical resection for BTC.
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Electroporation causes a temporal increase in cell membrane permeability and leads to prolonged changes in transmembrane voltage (TMV) in both excitable and non-excitable cells. However, the mechanisms of these TMV changes remain to be fully elucidated. To this end, we monitored TMV over 30 min after exposing two different cell lines to a single 100 µs electroporation pulse using the FLIPR Membrane Potential dye. In CHO-K1 cells, which express very low levels of endogenous ion channels, membrane depolarization following pulse exposure could be explained by nonselective leak current, which persists until the membrane reseals, enabling the cells to recover their resting TMV. In U-87 MG cells, which express many different ion channels, we unexpectedly observed membrane hyperpolarization following the initial depolarization phase, but only at 33 °C and not at 25 °C. We developed a theoretical model, supported by experiments with ion channel inhibitors, which indicated that hyperpolarization could largely be attributed to the activation of calcium-activated potassium channels. Ion channel activation, coupled with changes in TMV and intracellular calcium, participates in various physiological processes, including cell proliferation, differentiation, migration, and apoptosis. Therefore, our study suggests that ion channels could present a potential target for influencing the biological response after electroporation.
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OBJECTIVE: This study seeks to elucidate the expression, function, and clinical relevance of the T cell receptor interacting molecule (TRIM) within circulating CD4+T cell subsets in systemic lupus erythematosus (SLE) patients. METHODS: We assessed TRIM expression across distinct subpopulations of human peripheral blood mononuclear cells (PBMCs) through the analysis of publicly available single-cell RNA sequencing data. In addition, TRIM expression was investigated within CD4+T cell subsets of peripheral blood and spleens in mice. PBMCs were isolated from both SLE patients, healthy controls (HCs) and rheumatoid arthritis (RA) patients with subsequent measurement and comparative analysis of TRIM expression and functional molecules using flow cytometry. To gauge the clinical relevance of TRIM in SLE, correlation and ROC curve analyses were performed. RESULTS: In both healthy humans and mice, TRIM was higher expressed within CD4+T cell subsets, especially in naive CD4+T cells. TRIM+ Tregs exhibited lower Helios+ cells and CD45RA-FoxP3hi cells percentages compared to TRIM- Treg cells. TRIM+T cells demonstrated reduced granzyme B and perforin secretion and increased IFN-γ secretion in comparison to TRIM- T cells. Notably, the proportion of TRIM+CD4+T cells was diminished in SLE patients. The downregulation of TRIM+ in CD4+T cells positively correlated with diminished complement C3 and C1q levels and inversely correlated with CRP. The identification of TRIM-associated CD4 T cell subsets aids in distinguishing SLE patients from HCs and those with RA. CONCLUSIONS: Reduced TRIM expression is linked to abnormal CD4+T cell activation in SLE. TRIM-associated CD4+T cells may be implicated in the pathogenesis of SLE and hold potential for clinical diagnostic purposes.
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The kidney is poised to defend against development of metabolic alkalosis through non-adaptive mechanisms in the proximal nephron and adaptive processes in the distal nephron. Despite a prodigious capacity to excrete base, metabolic alkalosis is the most common acid-base disturbance in hospitalized patients. Development of this disorder requires pathophysiologic changes leading to generation of new HCO3- combined with an augmentation in the capacity of the kidney to reclaim filtered HCO3-. The initial approach to these patients is careful assessment of effective arterial blood volume focusing on the physical examination and urine electrolytes. Identifying the mechanisms by which the kidney's ability to correct alkalosis are perturbed provides an understanding of the clinical approach to differential diagnosis and appropriate treatment. While metabolic alkalosis is frequently not dangerous, in certain settings, metabolic alkalosis may contribute to mortality and should be aggressively managed.
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Fungal biosynthetic gene clusters often include genes encoding transmembrane proteins, which have been mostly thought to be transporters exporting the products. However, there is little knowledge about subcellular compartmentalization of transmembrane proteins essential for biosynthesis. Fungal mycotoxin cyclochlorotine is synthesized by non-ribosomal peptide synthetase, which is followed by modifications with three transmembrane UstYa-family proteins. Heterologous expression in Aspergillus oryzae revealed that total biosynthesis of cyclochlorotine requires additional two transporter proteins. Here, we investigated subcellular localizations of the five transmembrane proteins under heterologous expression in A. oryzae. Enhanced green fluorescent protein (EGFP) fusions to the transmembrane proteins, which were confirmed to normally function in cyclochlorotine production, were expressed together with organellar markers. All the transmembrane proteins exhibited localizations commonly in line of the trans-Golgi, endosomes, and vacuoles. This study suggests that subcellular compartmentalization of UstYa family proteins and transporters allows corporative functions of delivering intermediates and subsequent modifications, completing cyclochlorotine biosynthesis.
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PURPOSE: To improve the oral bioavailability of albendazole (ABZ), a series of albendazole-bile acid conjugates (ABCs) were synthesized. ABC's transmembrane transport mechanism and in vivo pharmacokinetic properties were preliminarily studied. METHODS: The transmembrane transport mechanism of ABCs was studied using the Caco-2 monolayer cell model and intestinal perfusion model. The concentration of ABCs and ABZ were evaluated using High-Performance Liquid Chromatography (HPLC) and HPLC-Mass Spectrometry (HPLC-MS/MS). RESULTS: Compared to ABZ, better permeability was observed for different types and concentrations of ABCs using the Caco-2 monolayer cell model, with ABC-C8 showing the highest permeability. The transmembrane transport of ABCs was affected by ASBT inhibitors, indicating an ASBT-mediated active transport mechanism. Additionally, introducing cholic acid resulted in ABZ no longer being a substrate for P-gp, MRP2, and BCRP, effectively reversing ABZ efflux. In vivo unidirectional intestinal perfusion results in rats showed that ABCs altered the absorption site of ABZ from the jejunum to the ileum. The absorption efficiency of ABCs in each intestinal segment was higher than that of ABZ, and the transmembrane transport efficiency decreased with increasing concentrations of ASBT inhibitors. This further confirmed the presence of both passive diffusion and ASBT-mediated active transport mechanisms in the transport of ABCs. The solubility of ABCs in gastric juice and pharmacokinetics in rats showed that ABZ-C4 exhibited enhanced solubility. Moreover, ABCs significantly increased oral bioavailability compared to ABZ, with ABC-C4 showing an approximately 31-fold increase in bioavailability. CONCLUSION: The transmembrane transport mechanism of ABCs involves a combination of ASBT-mediated active transport and passive diffusion. Moreover, the incorporation of BAs successfully reverses the efflux of ABZ by efflux proteins. Among the synthesized conjugates, ABC-C4 demonstrated superior dissolution behavior both in vitro and in vivo.
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BACKGROUND: CRISPR-Cas13a is renowned for its precise and potent RNA editing capabilities in cancer therapy. While various material systems have demonstrated efficacy in supporting CRISPR-Cas13a to execute cellular functions in vitro efficiently and specifically, the development of CRISPR-Cas13a-based therapeutic agents for intravesical instillation in bladder cancer (BCa) remains unexplored. METHODS: In this study, we introduce a CRISPR-Cas13a nanoplatform, which effectively inhibits PDL1 expression following intravesical instillation. This system utilizes a fusion protein CAST, created through the genetic fusion of CRISPR-Cas13 and the transmembrane peptide TAT. CAST acts as a potent transmembrane RNA editor and is assembled with the transepithelial delivery carrier fluorinated chitosan (FCS). Upon intravesical administration into the bladder, the CAST-crRNAa/FCS nanoparticles (NPs) exhibit remarkable transepithelial capabilities, significantly suppressing PDL1 expression in tumor tissues.To augment immune activation within the tumor microenvironment, we integrated a fenbendazole (FBZ) intravesical system (FBZ@BSA/FCS NPs). This system is formulated through BSA encapsulation followed by FCS coating, positioning FBZ as a powerful chemo-immunological agent. RESULTS: In an orthotropic BCa model, the FBZ@BSA/FCS NPs demonstrated pronounced tumor cell apoptosis, synergistically reduced PDL1 expression, and restructured the immune microenvironment. This culminated in an enhanced synergistic intravesical instillation approach for BCa. Consequently, our study unveils a novel RNA editor nanoagent formulation and proposes a potential synergistic therapeutic strategy. This approach significantly bolsters therapeutic efficacy, holding promise for the clinical translation of CRISPR-Cas13-based cancer perfusion treatments.
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Sistemas CRISPR-Cas , Neoplasias da Bexiga Urinária , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapia , Humanos , Animais , Administração Intravesical , Camundongos , Linhagem Celular Tumoral , FemininoRESUMO
The study analyses the performance of a pilot plant using a rotating hollow fibre (HF) membrane bioreactor system. The experiments evaluated the effect of operational parameters such as rotational speed, aeration strategies, and maintenance cleaning (MC) procedures on the efficiency of the system, in particular transmembrane pressure (TMP) and filtrate quality. The results indicate that the rotating membrane module reduces TMP increase and can operate for 48 days with satisfactory performance, even without aeration. This has the potential to significantly improve efficiency, resulting in significant energy savings. In addition, two MC methods, clean in air and clean in place, were tested and found to be efficient for weekly MC. It was observed that operating without aeration during colder seasons may not be effective. Therefore, adaptive strategies are needed to address seasonal temperature variations.
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Reatores Biológicos , Membranas Artificiais , Pressão , Eliminação de Resíduos Líquidos/métodos , Eliminação de Resíduos Líquidos/instrumentação , Projetos Piloto , Purificação da Água/métodos , Purificação da Água/instrumentaçãoRESUMO
Pancreatic malignancy is the fourth cause of cancer-related death in Western countries and is predicted to become the second leading cause of cancer-related mortality by 2030. The standard therapies (FOLFIRINOX and gemcitabine with nab-paclitaxel) are not resolutive because this type of cancer is also characterized by a high chemoresistance, due in part to the activity of the ATP Binding Cassette (ABC) pumps accounting for the reduction in the intracellular concentration of the drugs. In this work, we analyze the occurrence of single-nucleotide polymorphisms (SNPs) in the MDR-1 gene, in different pancreatic cancer cell lines, and in tissues from pancreatic cancer patients by DNA sequencing, as well as the expression levels of MDR-1 mRNA and protein, by qRT-PCR and Western Blot analysis. We found that gemcitabine-resistant cells, in conjunction with homozygosis of analyzed SNPs, showed high MDR-1 basal levels with further increases after gemcitabine treatment. Nevertheless, we did not observe in the human PDAC samples a correlation between the level of MDR-1 mRNA and protein expression and SNPs. Preliminary, we conclude that in our small cohort, these SNPs cannot be used as molecular markers for predicting the levels of MDR-1 mRNA/protein levels and drug responses in patients with PDAC.
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Subfamília B de Transportador de Cassetes de Ligação de ATP , Desoxicitidina , Resistencia a Medicamentos Antineoplásicos , Gencitabina , Neoplasias Pancreáticas , Polimorfismo de Nucleotídeo Único , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Masculino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Feminino , Pessoa de Meia-Idade , Idoso , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Transmembrane ion transport modality has received a widespread attention due to its apoptotic activation toward anticancer cell activities. In this study, G-quadruplex-based potassium-specific transmembrane channels have been developed to facilitate the intracellular K+ efflux, which perturbs the cellular ion homeostasis thereby inducing cancer cell apoptosis. Cholesterol-tag, a lipophilic anchor moiety, serves as a rudiment for the G-quadruplex immobilization onto the membrane, while G-quadruplex channel structure as a transport module permits ion binding and migration along the channels. A c-Myc sequence tagged with two-cholesterol is designed as a representative lipophilic G-quadruplex, which forms intramolecular parallel G-quadruplex with three stacks of G-quartets (Ch2-Para3). Fluorescence transport assay demonstrates Ch2-Para3 a high transport activity (EC50 = 10.9 × 10-6 m) and an ion selectivity (K+/Na+ selectivity ratio of 84). Ch2-Para3 mediated K+ efflux in cancer cells is revealed to purge cancer cells through K+ efflux-mediated cell apoptosis, which is confirmed by monitoring the changes in membrane potential of mitochondria, leakage of cytochrome c, reactive oxygen species yield, as well as activation of a family of caspases. The lipophilic G-quadruplex exhibits obvious antitumor activity in vivo without systemic toxicity. This study provides a functional scheme aimed at generating DNA-based selective artificial membrane channels for the purpose of regulating cellular processes and inducing cell apoptosis, which shows a great promising for anticancer therapy in the future.
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B cells surveil the body for foreign matter using their surface-expressed B cell antigen receptor (BCR), a tetrameric complex comprising a membrane-tethered antibody (mIg) that binds antigens and a signaling dimer (CD79AB) that conveys this interaction to the B cell. Recent cryogenic electron microscopy (cryo-EM) structures of IgM and IgG isotype BCRs provide the first complete views of their architecture, revealing that the largest interaction surfaces between the mIg and CD79AB are in their transmembrane domains (TMDs). These structures support decades of biochemical work interrogating the requirements for assembly of a functional BCR and provide the basis for explaining the effects of mutations. Here we report a focused saturating mutagenesis to comprehensively characterize the nature of the interactions in the mIg TMD that are required for BCR surface expression. We examined the effects of 600 single-amino-acid changes simultaneously in a pooled competition assay and quantified their effects by next-generation sequencing. Our deep mutational scanning results reflect a feature-rich TMD sequence, with some positions completely intolerant to mutation and others requiring specific biochemical properties such as charge, polarity or hydrophobicity, emphasizing the high value of saturating mutagenesis over, for example, alanine scanning. The data agree closely with published mutagenesis and the cryo-EM structures, while also highlighting several positions and surfaces that have not previously been characterized or have effects that are difficult to rationalize purely based on structure. This unbiased and complete mutagenesis dataset serves as a reference and framework for informed hypothesis testing, design of therapeutics to regulate BCR surface expression and to annotate patient mutations.
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Receptores de Antígenos de Linfócitos B , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Humanos , Mutação , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Antígenos CD79/genética , Antígenos CD79/metabolismo , Antígenos CD79/imunologia , Membrana Celular/metabolismo , CamundongosRESUMO
CD19-targeted chimeric antigen receptors (CAR) T cells are one of the most remarkable cellular therapies for managing B cell malignancies. However, long-term disease-free survival is still a challenge to overcome. Here, we evaluated the influence of different hinge, transmembrane (TM), and costimulatory CAR domains, as well as manufacturing conditions, cellular product type, doses, patient's age, and tumor types on the clinical outcomes of patients with B cell cancers treated with CD19 CAR T cells. The primary outcome was defined as the best complete response (BCR), and the secondary outcomes were the best objective response (BOR) and 12-month overall survival (OS). The covariates considered were the type of hinge, TM, and costimulatory domains in the CAR, CAR T cell manufacturing conditions, cell population transduced with the CAR, the number of CAR T cell infusions, amount of CAR T cells injected/Kg, CD19 CAR type (name), tumor type, and age. Fifty-six studies (3493 patients) were included in the systematic review and 46 (3421 patients) in the meta-analysis. The overall BCR rate was 56%, with 60% OS and 75% BOR. Younger patients displayed remarkably higher BCR prevalence without differences in OS. The presence of CD28 in the CAR's hinge, TM, and costimulatory domains improved all outcomes evaluated. Doses from one to 4.9 million cells/kg resulted in better clinical outcomes. Our data also suggest that regardless of whether patients have had high objective responses, they might have survival benefits from CD19 CAR T therapy. This meta-analysis is a critical hypothesis-generating instrument, capturing effects in the CD19 CAR T cells literature lacking randomized clinical trials and large observational studies.
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Antígenos CD19 , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Humanos , Fatores Etários , Antígenos CD19/imunologia , Imunoterapia Adotiva/métodos , Leucemia de Células B/terapia , Leucemia de Células B/imunologia , Leucemia de Células B/mortalidade , Linfoma de Células B/imunologia , Linfoma de Células B/terapia , Linfoma de Células B/mortalidade , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Resultado do TratamentoRESUMO
Currently, the role of cleft-lip and palate transmembrane protein-1-like (CLPTM1L) rs401681 in various tumor types, particularly lung cancer, has garnered significant attention. However, the findings across studies have shown discrepancies. The aim of the present meta-analysis was to provide a more nuanced understanding of the involvement of CLPTM1L rs401681 in lung cancer development. Several electronic databases were systematically searched, including PubMed, Cochrane Library, Embase, Medline, Wanfang, Google Scholar and Chinese National Knowledge Infrastructure. Odds ratios (ORs) and 95% confidence intervals (CIs) were synthesized using random-effects models. Heterogeneity of included studies was assessed using the I2 statistic and Q test. Sensitivity analysis was conducted to evaluate the stability of overall estimates. Moreover, Egger's test was utilized to detect potential publication bias. The collective ORs indicated a significant association between the CLPTM1L rs401681 polymorphism and susceptibility to lung cancer across various genetic comparisons. These encompass allele T vs. allele C (OR=0.93, 95% CI=0.88-0.99, P<0.001), TT + CT vs. CC (OR=0.91, 95% CI=0.87-0.96, P<0.001), TT vs. CC + CT (OR=0.88, 95% CI=0.80-0.96, P<0.001), TT vs. CC (OR=0.84, 95% CI=0.75-0.94, P<0.001) and CT vs. CC (OR=0.84, 95% CI=0.75-0.94, P<0.001). Examination through statistical Q test and I2 statistic revealed pronounced heterogeneity across four genetic comparisons (allele T vs. allele C, TT + CT vs. CC, TT vs. CC and CT vs. CC). Ethnical distinctions emerged as the primary, if not exclusive, sources of the significant heterogeneity. Upon stratification by ethnicity, a notable reduction in heterogeneity was discernible within the Caucasian demographic. However, heterogeneity persisted within the Asian population. Furthermore, lung cancer risks were statistically significantly decreased for individuals possessing allele T through all genetic comparisons within Caucasians; whereas among Asians, significant reduction was observed solely in the TT vs. CC comparison. The present meta-analysis uncovers a significant association between the CLPTM1L rs401681 polymorphism and altered susceptibility to lung cancer.
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Fine particulate matter (PM2.5) can damage airway epithelial barriers. The anion transport system plays a crucial role in airway epithelial barriers. However, the detrimental effect and mechanism of PM2.5 on the anion transport system are still unclear. In this study, airway epithelial cells and ovalbumin (OVA)-induced asthmatic mice were used. In transwell model, the adenosine triphosphate (ATP)-induced transepithelial anion short-circuit current (Isc) and airway surface liquid (ASL) significantly decreased after PM2.5 exposure. In addition, PM2.5 exposure decreased the expression levels of P2Y2R, CFTR and cytoplasmic free-calcium, but ATP can increase the expressions of these proteins. PM2.5 exposure increased the levels of Th2-related cytokines of bronchoalveolar lavage fluid, lung inflammation, collagen deposition and hyperplasisa of goblet cells. Interestingly, the administration of ATP showed an inhibitory effect on lung inflammation induced by PM2.5. Together, our study reveals that PM2.5 impairs the ATP-induced transepithelial anion Isc through downregulating P2Y2R/CFTR pathway, and this process may participate in aggravating airway hyperresponsiveness and airway inflammation. These findings may provide important insights on PM2.5-mediated airway epithelial injury.
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Asma , Regulador de Condutância Transmembrana em Fibrose Cística , Material Particulado , Receptores Purinérgicos P2Y2 , Animais , Camundongos , Receptores Purinérgicos P2Y2/metabolismo , Receptores Purinérgicos P2Y2/genética , Asma/metabolismo , Asma/patologia , Asma/tratamento farmacológico , Asma/induzido quimicamente , Asma/imunologia , Material Particulado/efeitos adversos , Material Particulado/toxicidade , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Trifosfato de Adenosina/metabolismo , Ovalbumina/imunologia , Transdução de Sinais/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação para Baixo/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologiaRESUMO
BACKGROUND/AIM: Interferon-induced trans-membrane protein 1 (IFITM1) is known to be involved in breast cancer progression. We aimed to investigate its role in estrogen receptor (ER)-positive breast cancer cells with wild-type p53 and tamoxifen-resistant breast cancer cells. MATERIALS AND METHODS: The ER-positive breast cancer cell lines, MCF-7 with wild-type p53 and T47D with mutant p53, were used. We established an MCF-7-derived tamoxifen-resistant cell line (TamR) by long-term culture of MCF-7 cells with 4-hydroxytamoxifen. RESULTS: IFITM1 inhibition in MCF-7 cells significantly decreased cell growth and migration. MCF-7 cells with suppression of IFITM1 using siRNA or ruxolitinib showed reduced cell viability after tamoxifen treatment compared with that in the control MCF-7 cells. Unexpectedly, mRNA and protein levels of IFITM1 were decreased in TamR cells compared with those in MCF-7 cells. TamR cells with suppression of IFITM1 using siRNA or ruxolitinib showed no change in cell viability after treatment with tamoxifen. P53 knockdown using siRNA reduced the mRNA levels of IRF9 and increased mRNA and protein levels of SOCS3 in MCF-7 cells, suggesting that loss or mutation of p53 can affect the induction of IFITM1 via the JAK/STAT signaling pathway in breast cancer. Furthermore, MCF-7 cells with p53 knockdown using siRNA showed no decrease in cell viability after tamoxifen treatment or IFITM1 inhibition, indicating that p53 status may be important for cell death after tamoxifen treatment or IFITM1 inhibition. CONCLUSION: IFITM1 inhibition may enhance the sensitivity to tamoxifen based on p53-dependent enhancement of IFN signaling in wild-type p53, ER-positive breast cancer cells.
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Antígenos de Diferenciação , Neoplasias da Mama , Proliferação de Células , Receptores de Estrogênio , Tamoxifeno , Proteína Supressora de Tumor p53 , Humanos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Feminino , Proliferação de Células/efeitos dos fármacos , Antígenos de Diferenciação/metabolismo , Receptores de Estrogênio/metabolismo , Tamoxifeno/farmacologia , Células MCF-7 , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
BACKGROUND: Glioblastoma (GBM) is a highly aggressive and fast-growing brain tumor, characterized by rapid progression, a very poor prognosis, and a high likelihood of recurrence. Thus, effective new therapeutic targets are urgently needed. Transmembrane proteins (TMEMs) have pro-cancer effects on multiple cancer types, but the mechanisms underlying the effects of TMEM17, particularly its role in GBM, remain unclear. METHODS: We conducted bioinformatics analyses and immunohistochemistry to evaluate the role of TMEM17 in a variety of cancer types. Functional assays were conducted included the Cell Counting Kit-8 assay, annexin V-FITC/PI double staining, 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, wound healing assay, transwell invasion assay, and dual luciferase assay. RESULTS: We found that TMEM17 is associated with a poor prognosis in GBM. Prognostic analyses confirmed that high TMEM17 expression predicted poorer survival, establishing its significance as an independent prognostic factor. Functional assays demonstrated that silencing TMEM17 in GBM cell lines inhibited proliferation and invasion, and induced apoptosis, underscoring its role in tumor aggressiveness. From a mechanistic perspective, we discovered that the Ying Yang 1 (YY1) transcription factor can bind to the promoter of TMEM17, regulating its upregulation. Regarding downstream mechanisms, knocking down TMEM17 inhibited the phosphoinositide 3-kinase/AKT pathway. These findings suggest that TMEM17 plays a significant role in GBM and may be a potential therapeutic target for this cancer. CONCLUSION: These data prove that TMEM17 plays a key role in the regulation of GBM and has great potential as a clinical therapeutic target for GBM.
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Neoplasias Encefálicas , Progressão da Doença , Glioblastoma , Proteínas de Membrana , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Linhagem Celular Tumoral , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proliferação de Células/genética , Fator de Transcrição YY1/metabolismo , Fator de Transcrição YY1/genética , Apoptose/genética , Masculino , Feminino , Prognóstico , Regulação Neoplásica da Expressão Gênica , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Lung adenocarcinoma (LUAD) is one of the major histopathological types of non-small cell lung cancer (NSCLC), including solid, acinar, lepidic, papillary and micropapillary subtypes. Increasing evidence has shown that micropapillary LUAD is positively associated with a higher percentage of driver gene mutations, a higher incidence of metastasis and a poorer prognosis, while lepidic LUAD has a relatively better prognosis. However, the novel genetic change and its underlying mechanism in the progression of micropapillary LUAD have not been exactly determined. METHODS: A total of 181 patients with LUAD who underwent surgery at the First Affiliated Hospital of Huzhou University from January 2020 to December 2022 were enrolled. Three predominant lepidic and three predominant micropapillary LUAD tissue samples were carried out using whole-exome sequencing. Comprehensive analysis of genomic variations and the difference between lepidic and micropapillary LUAD was performed. In addition, the TMEM229A Q200del mutation was verified using our cohort and TCGA-LUAD datasets. The correlations between the TMEM229A Q200del mutation and the clinicopathological characteristics of patients with LUAD were further analyzed. The functions and mechanisms of TMEM229A Q200del on NSCLC cell proliferation and migration were also determined. RESULTS: The frequency of genomic changes in patients with micropapillary LUAD was higher than that in patients with lepidic LUAD. Mutations in EGFR, ATXN2, C14orf180, MUC12, NOTCH1, and PKD1L2 were concomitantly detected in three predominant micropapillary and three predominant lepidic LUAD cases. The TMEM229A Q200del mutation was only mutated in lepidic LUAD. Additionally, the TMEM229A Q200del mutation had occurred in 16 (8.8%) patients, and not found TMEM229A R76H and M346T mutations in our cohort, while TMEM229A mutations (R76H, M346T, and Q200del) occurred only in 1.0% of the TCGA-LUAD cohort. Further correlation analysis between the TMEM229A Q200del mutation and clinicopathological characteristics suggested that a lower frequency of the Q200del mutation was significantly associated with positive lymph node metastasis, advanced TNM stage, positive cancer thrombus, and pathological features. Finally, overexpression of TMEM229A Q200del suppressed NSCLC cell proliferation and migration in vitro. Mechanistically, overexpression of TMEM229A and TMEM229A Q200del both reduced the expression level of phosphorylated (p)-ERK and p-AKT (Ser473), and the reduced protein level of p-ERK in the TMEM229A Q200del group was more pronounced compared to the TMEM229A group. CONCLUSION: Our results demonstrated that the TMEM229A Q200del mutant may play a protective role in the progression of LUAD via inactivating ERK pathway, providing a potential therapeutic target in LUAD.
Assuntos
Adenocarcinoma de Pulmão , Sequenciamento do Exoma , Neoplasias Pulmonares , Proteínas de Membrana , Mutação , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Feminino , Sequenciamento do Exoma/métodos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proliferação de Células/genética , Prognóstico , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular/genéticaRESUMO
Epithelial membrane protein 3 (EMP3) belongs to the peripheral myelin protein 22 kDa (PMP22) gene family, characterized by four transmembrane domains and widespread expression across various human tissues and organs. Other members of the PMP22 family, including EMP1, EMP2, and PMP22, have been linked to various cancers, such as glioblastoma, laryngeal cancer, nasopharyngeal cancer, gastric cancer, breast cancer, and endometrial cancer. However, few studies report on the function and relevance of EMP3 in tumorigenicity. Given the significant structural similarities among members of the PMP22 family, there are likely potential functional similarities as well. Previous studies have established the regulatory role of EMP3 in immune cells like T cells and macrophages. Additionally, EMP3 is found to be involved in critical signaling pathways, including HER-2/PI3K/Akt, MAPK/ERK, and TGF-beta/Smad. Furthermore, EMP3 is associated with cell cycle regulation, cellular proliferation, and apoptosis. Hence, it is likely that EMP3 participates in cancer development through these aforementioned pathways and mechanisms. This review aims to systematically examine and summarize the structure and function of EMP3 and its association to various cancers. EMP3 is expected to emerge as a significant biological marker for tumor prognosis and a potential target in cancer therapeutics.
Assuntos
Biomarcadores Tumorais , Glicoproteínas de Membrana , Terapia de Alvo Molecular , Neoplasias , Humanos , Biomarcadores Tumorais/metabolismo , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/genética , Prognóstico , Terapia de Alvo Molecular/métodos , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Transdução de SinaisRESUMO
Gastrointestinal cancer (GIC) is a common and widespread form of tumor, with colonoscopy and upper gastrointestinal endoscopy available to detect relevant precancerous polyps and lesions. However, many patients are already in the late stages when first diagnosed with such cancer, resulting in a poor prognosis. Thus, it is necessary to explore new methods and research directions in order to improve the treatment of GIC. Given the specific nature of the gastrointestinal tract, research should focus on the mechanisms of various inflammations and the interactions between food entering and exiting from the gastrointestinal tract and cancer cells. Interestingly, six transmembrane epithelial antigens of the prostates (STEAPs) have been found to be significantly linked to the progression of malignant tumors, associated with intracellular oxidative stress and playing a major role in inflammation with their structure and function. This paper explores the mechanism of STEAPs in the inflammatory response of GIC, providing a theoretical basis for the prevention and early intervention of GIC. The basic properties of the STEAP family as metal reductase are also explained. When it comes to intervention for GIC prevention, STEAPs can affect the activity of Fe3+, Cu2+ reductase and regulate metal ion uptake in vivo, participating in inflammation-related iron and copper homeostasis. Thus, the mechanism of STEAPs on inflammation is of important value in the prevention of GIC.
RESUMO
Bladder cancer is a urological tumor with high rates of recurrence despite recent advances in novel therapies. Many proteins involved in the molecular mechanisms are currently an enigma, especially the transmembrane 9 superfamily member 1 which has an unclear function. Wei et al published the function and mechanism of this protein, and showed that it could participate in the proliferation, migration and invasion of tumor cells in bladder cancer, therefore treatments directed against this protein may be beneficial in avoiding this condition.