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Small-cell lung cancer (SCLC) accounts for nearly 15% of all lung cancers. Although patients respond to first-line therapy readily, rapid relapse is inevitable, with few treatment options in the second-line setting. Here, we describe SCLC cell lines harboring amplification of MYC and MYCN but not MYCL1 or non-amplified MYC cell lines exhibit superior sensitivity to treatment with the pan-BET bromodomain protein inhibitor mivebresib (ABBV075). Silencing MYC and MYCN partially rescued SCLC cell lines harboring these respective amplifications from the antiproliferative effects of mivebresib. Further characterization of genome-wide binding of MYC, MYCN, and MYCL1 uncovered unique enhancer and epigenetic preferences. Implications: Our study suggests that chromatin landscapes can establish cell states with unique gene expression programs, conveying sensitivity to epigenetic inhibitors such as mivebresib.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Línea Celular Tumoral , Amplificación de Genes , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteína Proto-Oncogénica N-Myc/genética , Proteína Proto-Oncogénica N-Myc/metabolismo , Proteínas que Contienen Bromodominio , Proteínas , Piridonas , SulfonamidasRESUMEN
Prostate cancer (PCa) is the most common malignancy among men worldwide. The cell division cycle 42 effector protein 4 (CDC42EP4) functions downstream of CDC42, yet its role and molecular mechanisms in PCa remain unexplored. This study aimed to elucidate the role of CDC42EP4 in the progression of PCa and its underlying mechanisms. Bioinformatical analysis indicated that CDC42EP4 expression was significantly lower in PCa tissue compared to normal prostate tissue. Cellular phenotyping analysis suggested that CDC42EP4 markedly inhibited the proliferation, migration, and invasion of PCa cells. Xenograft tumor assays further demonstrated that CDC42EP4 suppressed the growth of PCa cells in vivo. Mechanistically, the study established that CDC42EP4 inhibited the ERK pathway in PCa cells. Additionally, the ERK pathway inhibitor PD0325901 was employed, revealing that PD0325901 significantly nullified the effects of CDC42EP4 on PCa cell proliferation, migration, and invasion. Collectively, our findings demonstrate that CDC42EP4 acts as a critical tumor suppressor gene, inhibiting PCa cell proliferation, migration, and invasion through the ERK pathway, thereby presenting potential targets for PCa therapy.
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Movimiento Celular , Proliferación Celular , Sistema de Señalización de MAP Quinasas , Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Animales , Línea Celular Tumoral , Ratones , Progresión de la Enfermedad , Ratones Desnudos , Regulación Neoplásica de la Expresión Génica , Invasividad Neoplásica/genéticaRESUMEN
The problem of drug resistance due to long-term use of antibiotics has been a concern for years. As this problem grows worse, infections caused by multiple bacteria are expanding rapidly and are extremely detrimental to human health. Antimicrobial peptides (AMPs) are a good alternative to current antimicrobials with potent antimicrobial activity and unique antimicrobial mechanisms, which have advantages over traditional antibiotics in fighting against drug-resistant bacterial infections. Currently, researchers have conducted clinical investigations on AMPs for drug-resistant bacterial infections while integrating new technologies in the development of AMPs, such as changing amino acid structure of AMPs and using different delivery methods for AMPs. This article introduces the basic properties of AMPs, deliberates the mechanism of drug resistance in bacteria and the therapeutic mechanism of AMPs. The current disadvantages and advances of AMPs in combating drug-resistant bacterial infections are also discussed. This article provides important insights into the research and clinical application of new AMPs for drug-resistant bacterial infections.
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Antiinfecciosos , Infecciones Bacterianas , Humanos , Péptidos Antimicrobianos , Péptidos Catiónicos Antimicrobianos/farmacología , Péptidos Catiónicos Antimicrobianos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Antiinfecciosos/uso terapéutico , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Bacterias/metabolismoRESUMEN
Prostate cancer (PCa) is one of the most common malignancies in men. Ribosomal protein L22-like1 (RPL22L1), a component of the ribosomal 60 S subunit, is associated with cancer progression, but the role and potential mechanism of RPL22L1 in PCa remain unclear. The aim of this study was to investigate the role of RPL22L1 in PCa progression and the mechanisms involved. Bioinformatics and immunohistochemistry analysis showed that the expression of RPL22L1 was significantly higher in PCa tissues than in normal prostate tissues. The cell function analysis revealed that RPL22L1 significantly promoted the proliferation, migration and invasion of PCa cells. The data of xenograft tumour assay suggested that the low expression of RPL22L1 inhibited the growth and invasion of PCa cells in vivo. Mechanistically, the results of Western blot proved that RPL22L1 activated PI3K/Akt/mTOR pathway in PCa cells. Additionally, LY294002, an inhibitor of PI3K/Akt pathway, was used to block this pathway. The results showed that LY294002 remarkably abrogated the oncogenic effect of RPL22L1 on PCa cell proliferation and invasion. Taken together, our study demonstrated that RPL22L1 is a key gene in PCa progression and promotes PCa cell proliferation and invasion via PI3K/Akt/mTOR pathway, thus potentially providing a new target for PCa therapy.
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Próstata , Neoplasias de la Próstata , Masculino , Humanos , Próstata/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Línea Celular Tumoral , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias de la Próstata/patología , Proliferación Celular/genética , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Movimiento Celular/genéticaRESUMEN
Microcystinleucine arginine (MCLR) is an environmental toxin produced by cyanobacteria and is considered to be a potent carcinogen. However, to the best of our knowledge, the effect of MCLR on colorectal cancer (CRC) cell proliferation has never been studied. The aim of the present study was to investigate the effect of MCLR on CRC cell proliferation and the underlying mechanisms. Firstly, a Cell Counting Kit8 (CCK8) assay was conducted to determine cell viability at different concentrations, and 50 nM MCLR was chosen for further study. Subsequently, a longer CCK8 assay and a cell colony formation assay showed that MCLR promoted SW620 and HT29 cell proliferation. Furthermore, western blotting analysis showed that MCLR significantly upregulated protein expression of PI3K, pAkt (Ser473), pGSK3ß (Ser9), ßcatenin, cmyc and cyclin D1, suggesting that MCLR activated the PI3K/Akt and Wnt/ßcatenin pathways in SW620 and HT29 cells. Finally, the pathway inhibitors LY294002 and ICG001 were used to validate the role of the PI3K/Akt and Wnt/ßcatenin pathways in MCLRaccelerated cell proliferation. The results revealed that MCLR activated Wnt/ßcatenin through the PI3K/Akt pathway to promote cell proliferation. Taken together, these data showed that MCLR promoted CRC cell proliferation by activating the PI3K/Akt/Wnt/ßcatenin pathway. The present study provided a novel insight into the toxicological mechanism of MCLR.
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Neoplasias Colorrectales , beta Catenina , Humanos , Leucina/farmacología , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Microcistinas/toxicidad , Arginina , Proliferación Celular , Proteínas Tirosina Quinasas ReceptorasRESUMEN
FN-1501 is a potent FLT3 inhibitor with antitumor activity. A phase 1 trial of FN-1501 monotherapy in patients with advanced solid tumors and R/R AML is in progress. Since one of the primary causes of multidrug resistance (MDR) is the overexpression of ATP-binding cassette superfamily B member 1 (ABCB1), the objective of this study was to investigate the potential relationship between FN-1501 and the ABCB1 transporter. We found ABCB1 overexpressing-cancer cells conferred FN-1501 resistance, which could be reversed by an ABCB1 inhibitor. Molecular docking study revealed that FN-1501 docked the ligand binding site with an affinity score of -9.77 kcal/mol, denoting a strong interaction between FN-1501 and ABCB1. Additionally, the ABCB1 ATPase assay indicated that FN-1501 could significantly stimulate ABCB1 ATPase activity. Furthermore, we observed a similar trend of ABCB1-facilated FN-1501 resistance in tumor-bearing mice model. In sum, we demonstrate that FN-1501 is a substrate of ABCB1 transporter from both in vivo and in vitro studies. Therefore, our findings provide new insight on the mechanism of chemoresistance due to ABCB1 overexpression.
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Microcystin-LR (MC-LR) is an environmental toxin that is synthesized by cyanobacteria and considered a potential human carcinogen. However, the role of MC-LR in prostate cancer progression has not been elucidated. The purpose of this study was to investigate the effect of MC-LR on prostate cancer cell invasion and its underlying mechanisms. Transwell assay was performed, and the result showed that MC-LR increased DU145 cell invasion in a concentration-dependent manner. The result of Western blot showed that MC-LR promoted ERK phosphorylation, while enhancing VASP and ezrin phosphorylation. Moreover, PD0325901 was used to verify the role of the ERK/VASP/ezrin axis in MC-LR-promoted cell invasion. The results revealed that MC-LR promoted microfilament rearrangement and cell invasion by activating the ERK/VASP/ezrin pathway in DU145 cells. Finally, in vivo assay was performed, and the result suggested that MC-LR promoted p-ERK, p-VASP and p-ezrin expression and local invasion in nude mice model. Taken together, our data proved that MC-LR induced microfilament rearrangement and cell invasion by activating the ERK/VASP/ezrin pathway in DU145 cells.
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Citoesqueleto de Actina , Microcistinas , Animales , Proteínas del Citoesqueleto , Masculino , Toxinas Marinas , Ratones , Ratones Desnudos , Microcistinas/toxicidadRESUMEN
Dual bromodomain BET inhibitors that bind with similar affinities to the first and second bromodomains across BRD2, BRD3, BRD4, and BRDT have displayed modest activity as monotherapy in clinical trials. Thrombocytopenia, closely followed by symptoms characteristic of gastrointestinal toxicity, have presented as dose-limiting adverse events that may have prevented escalation to higher dose levels required for more robust efficacy. ABBV-744 is a highly selective inhibitor for the second bromodomain of the four BET family proteins. In contrast to the broad antiproliferative activities observed with dual bromodomain BET inhibitors, ABBV-744 displayed significant antiproliferative activities largely although not exclusively in cancer cell lines derived from acute myeloid leukemia and androgen receptor positive prostate cancer. Studies in acute myeloid leukemia xenograft models demonstrated antitumor efficacy for ABBV-744 that was comparable with the pan-BET inhibitor ABBV-075 but with an improved therapeutic index. Enhanced antitumor efficacy was also observed with the combination of ABBV-744 and the BCL-2 inhibitor, venetoclax compared with monotherapies of either agent alone. These results collectively support the clinical evaluation of ABBV-744 in AML (Clinical Trials.gov identifier: NCT03360006).
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Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Piridinas/farmacología , Pirroles/farmacología , Sulfonamidas/farmacología , Animales , Antineoplásicos/farmacología , Apoptosis , Proliferación Celular , Quimioterapia Combinada , Femenino , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) remains one of the most vital factors leading to multidrug resistance (MDR). It is important to enhance the effect and bioavailability of chemotherapeutic drugs that are substrates of ABCB1 transporter in ABCB1-overexpression cancer cells and reverse ABCB1-mediated MDR. Previous, we uncovered that the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is a potent reversal agent to overcomes paclitaxel resistance in ABCB1-overexpressing cells and tumors. In this study, we explored whether RN486, another BTK inhibitor, was competent to surmount ABCB1-mediated MDR and promote relevant cancer chemotherapy. We found that RN486 significantly increased the efficacy of paclitaxel and doxorubicin in both drug-selected carcinoma cells and transfected cells overexpressing ABCB1. Mechanistic studies indicated that RN486 dramatically attenuated the drug efflux activity of ABCB1 transporter without altering its expression level or subcellular localization. The ATPase activity of ABCB1 transporter was not affected by low concentrations but stimulated by high concentrations of RN486. Moreover, an interaction between RN486 with ABCB1 substrate-binding and inhibitor binding sites was verified by in silico docking simulation. The results from our study suggest that RN486 could be a reversal agent and could be used in the novel combination therapy with other antineoplastic drugs to conquer MDR-mediated by ABCB1 transporter in clinics.
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Hepatocellular carcinoma (HCC), a common malignancy in China and globally, is primarily treated through surgical resection and liver transplantation, with chemotherapy as a significant synergistic option. Adenine (Ade), a nucleobase, exhibits antitumor effects by blocking human hepatic carcinoma cells in S phase and inhibiting tumor cell proliferation. However, its use is limited owing to its low solubility, poor targeting ability, and nephrotoxicity. Therefore, liver-targeting drug delivery systems have attracted considerable attention for the treatment of HCC. In this study, we explored the liver-targeting efficacy and antitumor effect of adenine-loaded glycyrrhetinic acid-modified hyaluronic acid (Ade/GA-HA) nanoparticles in vitro and in vivo. The GA-HA nanoparticles possessed obvious targeting specificity toward liver cancer cells, which was mainly achieved by the specific binding of the GA ligand to the GA receptor that was highly expressed on the liver cell membrane. In vitro and in vivo results showed that Ade/GA-HA nanoparticles could inhibit liver cancer cell proliferation and migration, promote apoptosis, and significantly inhibit the growth of tumor tissues. Altogether, this study is the first to successfully demonstrate that the targeting activity and antitumor effect of Ade against HCC are enhanced by using GA-HA nanoparticles in vitro and in vivo.
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Adenina/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Ácido Glicirretínico/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Nanopartículas/administración & dosificación , Adenina/metabolismo , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/metabolismo , Carcinoma Hepatocelular/metabolismo , Femenino , Ácido Glicirretínico/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Carga Tumoral/efectos de los fármacos , Carga Tumoral/fisiologíaRESUMEN
Multidrug resistance (MDR) is a major challenge in the treatment of tumors. It refers to cancer cells become resistant to not only the therapeutic drug, but also cross-resistant to multiple drugs with distinct structures and mechanisms of action when they are exposed to a drug for a period of time. An essential mechanism of MDR is the aberrant expression and function of ATP-binding cassette (ABC) transporters. Therefore, blocking the function of ABC transporters has the therapeutic potential in reversing MDR. The hdm2 oncogene product, HDM2 (also known as MDM2), is an important negative regulator of the p53 tumor suppressor. NVP-CGM097 is an HDM2 inhibitor that can inhibit the proliferation of tumor cells and is currently under clinical trials. In this study, we evaluate whether NVP-CGM097 could reverse ABCB1-mediated MDR. The results of reversal experiment showed that NVP-CGM097 remarkably reversed ABCB1-mediated MDR but not ABCG2-mediated MDR. The results of Western blot and immunofluorescence suggested that the level of expression and subcellular localization of ABCB1 protein were not significantly altered by NVP-CGM097. Mechanism studies indicated that NVP-CGM097 could reverse ABCB1-mediated MDR by directly blocking the ABCB1-mediated drug efflux and raising the accumulation of chemotherapeutic drugs in cancer cells. ATPase analysis showed that low concentration NVP-CGM097 activates ABCB1 ATPase activity while high concentration NVP-CGM097 inhibited ABCB1-associated ATPase. Docking study indicated that NVP-CGM097 tended to bind to the inhibitory site, which led to slight but critical conformational changes in the transporter and reduced the ATPase activity. Overall, our study demonstrates that NVP-CGM097 can be used in conjunction with chemotherapeutic drugs to counteract MDR and improve the antitumor responses.
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ABCB1 overexpression is known to contribute to multidrug resistance (MDR) in cancers. Therefore, it is critical to find effective drugs to target ABCB1 and overcome MDR. Erdafitinib is a tyrosine kinase inhibitor (TKI) of fibroblast growth factor receptor (FGFR) that is approved by the FDA to treat urothelial carcinoma. Previous studies have demonstrated that some TKIs exhibit MDR reversal effect. In this work, we examined whether erdafitinib could reverse MDR mediated by ABCB1. The results of reversal experiments showed that erdafitinib remarkably reversed ABCB1-mediated MDR without affecting ABCG2-mediated MDR. The results of immunofluorescence and Western blot analysis demonstrated that erdafitinib did not affect the expression of ABCB1 or its cellular localization. Further study revealed that erdafitinib inhibited ABCB1 efflux function leading to increasing intracellular drug accumulation, thereby reversing MDR. Furthermore, ATPase assay indicated that erdafitinib activated the ABCB1 ATPase activity. Docking study suggested that erdafitinib interacted with ABCB1 on the drug-binding sites. In summary, this study demonstrated that erdafitinib can reverse MDR mediated by ABCB1, suggesting that combination of erdafitinib and ABCB1-substrate conventional chemotherapeutic drugs could potentially be used to overcome MDR mediated by ABCB1.
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Liposomes have been widely used as drug carriers in both biomedical research and for clinical applications, allowing the stabilisation of therapeutic compounds and overcoming obstacles to cellular and tissue uptake. However, liposomes still have low targeting efficiency, resulting in insufficient killing of tumour cells and unnecessary damage to normal cells. In this study, glycyrrhetinic acid (GA) and peanut agglutinin (PNA) were used as ligands to prepare dual-ligand-modified doxorubicin-loaded liposomes (DOX-GA/PNA-Lips) to enhance the targeting accuracy and efficacy of drug delivery against malignant liver cancer. PNA and GA modification enhanced the binding ability of liposomes to liver cancer cells, leading to excellent tissue and cell targeting of DOX-GA/PNA-Lips. DOX-GA/PNA-Lips showed an effective anti-tumour effect in vivo and in vitro, with its targeted delivery facilitating attenuation of the toxic side effects of DOX. These results demonstrated that dual-ligand-modified liposomes may provide an effective strategy for the treatment of hepatocellular carcinoma.
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Carcinoma Hepatocelular/patología , Doxorrubicina/análogos & derivados , Ácido Glicirretínico , Liposomas/química , Neoplasias Hepáticas/patología , Aglutinina de Mani , Animales , Antibióticos Antineoplásicos/administración & dosificación , Doxorrubicina/química , Humanos , Ratones , Ratones Desnudos , Polietilenglicoles/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Preeclampsia (PE) is a life-threatening disorder of human pregnancy affecting 5-8% of all pregnancies. Currently, PE remains an elusive complicated and heterogenous medical condition with no early marker or symptoms is recognized for this serious pregnancy complications. Here, we profiled the plasma miRNA expression patterns associated with preeclampsia and found 16 miRNAs were deregulated (p < 0.01) in patients who later developed PE. Circulating hsa-miR-125b was aberrantly upregulated in early pregnancy and significantly reduced after delivery in preeclampsia. We then investigated the underlying molecular mechanisms between miR-125b and PE in vitro. We found that upregulated miR-125b can target KCNA1 to inhibit trophoblast invasion in human trophoblast cells. Moreover, overexpression of miR-125b in HUVECs impaired endothelial cell function through GPC1. The findings indicated that upregulated miR-125b leads to impaired placentation, and an increased risk of preeclampsia, Our studies provide novel insights into the underlying mechanisms on the association of miR-125b in early pregnancy and risk of PE, miR-125b might be a more specific predictive marker and a safe therapeutic target for treating patients with PE.
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BACKGROUND: Tumors comprise a complex microenvironment of interacting malignant and stromal cell types. Much of our understanding of the tumor microenvironment comes from in vitro studies isolating the interactions between malignant cells and a single stromal cell type, often along a single pathway. RESULT: To develop a deeper understanding of the interactions between cells within human lung tumors, we perform RNA-seq profiling of flow-sorted malignant cells, endothelial cells, immune cells, fibroblasts, and bulk cells from freshly resected human primary non-small-cell lung tumors. We map the cell-specific differential expression of prognostically associated secreted factors and cell surface genes, and computationally reconstruct cross-talk between these cell types to generate a novel resource called the Lung Tumor Microenvironment Interactome (LTMI). Using this resource, we identify and validate a prognostically unfavorable influence of Gremlin-1 production by fibroblasts on proliferation of malignant lung adenocarcinoma cells. We also find a prognostically favorable association between infiltration of mast cells and less aggressive tumor cell behavior. CONCLUSION: These results illustrate the utility of the LTMI as a resource for generating hypotheses concerning tumor-microenvironment interactions that may have prognostic and therapeutic relevance.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Comunicación Celular , Neoplasias Pulmonares/metabolismo , Receptor Cross-Talk , Microambiente Tumoral , Adenocarcinoma/metabolismo , Línea Celular Tumoral , Fibroblastos/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Cultivo Primario de CélulasRESUMEN
Microcystin-leucine arginine (MC-LR) is a potent tumor initiator that can induce malignant cell transformation. Cellular mechanical characteristics are pivotal parameters that are closely related to cell invasion. The aim of this study is to determine the effect of MC-LR on mechanical parameters, microfilament, and cell invasion in DU145 and WPMY cells. Firstly, 10 µM MC-LR was selected as the appropriate concentration via cell viability assay. Subsequently, after MC-LR treatment, the cellular deformability and viscoelastic parameters were tested using the micropipette aspiration technique. The results showed that MC-LR increased the cellular deformability, reduced the cellular viscoelastic parameter values, and caused the cells to become softer. Furthermore, microfilament and microfilament-associated proteins were examined by immunofluorescence and Western blot, respectively. Our results showed that MC-LR induced microfilament reorganization and increased the expression of p-VASP and p-ezrin. Finally, the impact of MC-LR on cell invasion was evaluated. The results revealed that MC-LR promoted cell invasion. Taken together, our results suggested that mechanical changes and microfilament reorganization were involved in MC-LR-promoted cell invasion in DU145 and WPMY cells. Our data provide novel information to explain the toxicological mechanism of MC-LR.
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Prostate cancer (PCa) is one of the most common malignant tumors worldwide. The aim of the present study was to determine potential diagnostic and prognostic biomarkers for PCa. The GSE103512 dataset was downloaded, and the differentially expressed genes (DEGs) were screened. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) analyses of DEGs were performed. The result of GO analysis suggested that the DEGs were mostly enriched in 'carboxylic acid catabolic process', 'cell apoptosis', 'cell proliferation' and 'cell migration'. KEGG analysis results indicated that the DEGs were mostly concentrated in 'metabolic pathways', 'ECM-receptor interaction', the 'PI3K-Akt pathway' and 'focal adhesion'. The PPI analysis results showed that Golgi membrane protein 1 (GOLM1), melanoma inhibitory activity member 3 (MIA3), ATP citrate lyase (ACLY) and G protein subunit ß2 (GNB2) were the key genes in PCa, and the Module analysis revealed that they were associated with 'ECM-receptor interaction', 'focal adhesion', the 'PI3K-Akt pathway' and the 'metabolic pathway'. Subsequently, the gene expression was confirmed using Gene Expression Profiling Interactive Analysis and the Human Protein Atlas. The results demonstrated that GOLM1 and ACLY expression was significantly upregulated (P<0.05) in PCa compared with that in normal tissues. Receiver operating characteristic and survival analyses were performed. The results showed that area under the curve values of these genes all exceeded 0.85, and high expression of these genes was associated with poor survival in patients with PCa. In conclusion, this study identified GOLM1 and ACLY in PCa, which may be potential diagnostic and prognostic biomarker of PCa.
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The elaborate modulation of the transforming growth factor ß (TGF-ß) superfamily signaling network plays an essential role in tooth morphogenesis and differentiation. In our previous studies, we have demonstrated that TGF-ß1 promotes enamel mineralization and maturation using TGF-ß1 gene conditional knockout (TGF-ß1-cKO) mice. However, the specific regulatory mechanisms of TGF-ß1 during enamel development remain unclear. Furthermore, we have previously found that the expression of WD repeat-containing protein 72(WDR72)in mouse enamel epithelium is decreased significantly in the absence of TGF-ß1. Therefore, the aim of the present study was to investigate how TGF-ß1 affects amelogenesis by regulating the expression of Wdr72. Histological examination showed that the absence of TGF-ß1 in ameloblastic epithelial cells resulted in a reduction in enamel mineralization and a delay in enamel matrix protein absorption. TGF-ß1, Runt-related transcription factor 2(RUNX2) and WDR72 were revealed to be colocalized in ameloblasts by immunohistochemistry, and it was also found that the expression of Runx2 and Wdr72 was markedly different between TGF-ß1-cKO mice and wild type(TGF-ß1-WT)mice. In addition, the effect of exogenous TGF-ß1 on Wdr72 was more significant when RUNX2 was present than when RUNX2 was absent. Furthermore, we found that there were binding sites for RUNX2 on the promoter of Wdr72 and that Wdr72 expression was regulated by RUNX2. Collectively, our results suggest that TGF-ß1 affects enamel mineralization by modulating RUNX2 and thus affecting the expression of Wdr72.
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Ameloblastos/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Esmalte Dental/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Minerales/metabolismo , Proteínas/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Amelogénesis , Animales , Secuencia de Bases , Sitios de Unión , Linaje de la Célula , Esmalte Dental/diagnóstico por imagen , Células Epiteliales/metabolismo , Ratones Noqueados , Regiones Promotoras Genéticas , Proteínas/genética , Germen Dentario/metabolismoRESUMEN
Emerging evidence suggests that some members of the tripartite motif (TRIM) family play a crucial role in antiretroviral. However, the chicken TRIM62 antiretroviral activity is unknown. Avian leukosis virus subgroup J (ALV-J) is an avian retrovirus mainly inducing tumor formation and immunosuppression. The purpose of the study was to explore chicken TRIM62's role in ALV-J replication. In this study, we first tested the RNA expression of ALV-J and TRIM62 in chicken embryo fibroblasts (CEFs) cells infected with ALV-J by qRT-PCR. The result showed that ALV-J infection affected TRIM62 RNA expression, first upregulation and then downregulation, with the time course infection of ALV-J. Then, we silenced and overexpressed the TRIM62 to evaluate the effect of TRIM62 on ALV-J replication by qRT-PCR. We found that the knockdown of TRIM62 in CEF cells with shRNA targeting SPRY domain enhanced the viral replication more significantly than that with shRNA targeting coiled coil/unstructured domain, and overexpression of TRIM62 inhibited the viral replication. Further, we detected the effect of the domain deletion on TRIM62's antiviral activity. The result demonstrated that deletion of RING, B-box, coiled-coil domains partially abolished TRIM62's antiviral activity, while SPRY domain deletion resulted in the disappearance of antiviral activity of TRIM62. Taken together, our findings strongly suggested that TRIM62 plays an important role in the restriction of ALV-J replication, and SPRY domain is a prerequisite for the antiviral activity of TRIM62.
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Virus de la Leucosis Aviar/fisiología , Proteínas Aviares/metabolismo , Dominio B30.2-SPRY/genética , Pollos/virología , Proteínas de Motivos Tripartitos/metabolismo , Replicación Viral , Animales , Embrión de Pollo , Fibroblastos/virología , Regulación de la Expresión GénicaRESUMEN
Amphiphilic peptides modified by molecular design can self-assemble into specific nanostructures with interesting applications in the fields of biomedicine and biotechnology. Lysyl oxidase (LO) is ubiquitous in human serum. However, enzymatic self-assembly of amphiphilic peptides remains a challenge for lipid-soluble drug delivery under the induction of LO. Here, we designed a positively charged amphiphilic peptide, A6K2, that could stably self-assemble to form nanovesicles. The lysine in the peptide molecule could be covalently cross-linked under enzyme catalysis, and the major transition was from random coil to ß-sheet secondary structures, eventually leading to the destruction of the peptide nanovesicles. The lipid-soluble antitumour drug doxorubicin (DOX) as a model drug could be loaded into the hydrophobic core of the nanovesicles formed by the amphiphilic peptide A6K2, even though DOX was not covalently linked to the peptide monomer. The amount of DOX-encapsulated A6K2 nanovesicles in human hepatocellular carcinoma BEL-7402 cells was significantly higher than that in human liver L02 cells, indicating excellent selectivity. The amphiphilic peptide A6K2 inhibited tumour cell growth and had low cytotoxicity to mammalian cells, and it showed antibacterial activity against G+ and G- bacteria. These advantages make enzymatic self-assembling A6K2 nanovesicles of great interest in drug delivery for biomedical applications.