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1.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33800494

RESUMEN

Malignant pleural mesothelioma (MPM) is a fatal tumor lacking effective therapies. The characterization of overexpressed genes could constitute a strategy for identifying drivers of tumor progression as targets for novel therapies. Thus, we performed an integrated gene-expression analysis on RNAseq data of 85 MPM patients from TCGA dataset and reference samples from the GEO. The gene list was further refined by using published studies, a functional enrichment analysis, and the correlation between expression and patients' overall survival. Three molecular signatures defined by 15 genes were detected. Seven genes were involved in cell adhesion and extracellular matrix organization, with the others in control of the mitotic cell division or apoptosis inhibition. Using Western blot analyses, we found that ADAMTS1, PODXL, CIT, KIF23, MAD2L1, TNNT1, and TRAF2 were overexpressed in a limited number of cell lines. On the other hand, interestingly, CTHRC1, E-selectin, SPARC, UHRF1, PRSS23, BAG2, and MDK were abundantly expressed in over 50% of the six MPM cell lines analyzed. Thus, these proteins are candidates as drivers for sustaining the tumorigenic process. More studies with small-molecule inhibitors or silencing RNAs are fully justified and need to be undertaken to better evaluate the cancer-driving role of the targets herewith identified.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias , Neoplasias Pleurales , Femenino , Humanos , Masculino , /metabolismo , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Neoplasias Pleurales/genética , Neoplasias Pleurales/metabolismo
2.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33802212

RESUMEN

Targetable alterations in cancer offer novel opportunities to the drug discovery process. However, pre-clinical testing often requires solubilization of these drugs in cosolvents like dimethyl sulfoxide (DMSO). Using a panel of cell lines commonly used for in vitro drug screening and pre-clinical testing, we explored the DMSO off-target effects on functional signaling networks, drug targets, and downstream substrates. Eight Non-Small Cell Lung Cancer (NSCLC) cell lines were incubated with three concentrations of DMSO (0.0008%, 0.002%, and 0.004% v/v) over time. Expression and activation levels of 187 proteins, of which 137 were kinases and downstream substrates, were captured using the Reverse Phase Protein Array (RPPA). The DMSO effect was heterogeneous across cell lines and varied based on concentration, exposure time, and cell line. Of the 187 proteins measured, all were statistically different in at least one comparison at the highest DMSO concentration, followed by 99.5% and 98.9% at lower concentrations. Only 46% of the proteins were found to be statistically different in more than 5 cell lines, indicating heterogeneous response across models. These cell line specific alterations modulate response to in vitro drug screening. Ultra-low DMSO concentrations have broad and heterogeneous effects on targetable signaling proteins. Off-target effects need to be carefully evaluated in pre-clinical drug screening and testing.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Dimetilsulfóxido/farmacología , Sistemas de Liberación de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/biosíntesis , Transducción de Señal/efectos de los fármacos , Células A549 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología
3.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-33800754

RESUMEN

The natural isoquinoline alkaloid Berberine (BBR) has been shown to possess several therapeutic effects, including anticancer activity. Different BBR derivatives have been designed and synthesized in order to obtain new compounds with enhanced anticancer efficacy. We previously showed that intraperitoneal (IP) administration of the BBR-derived NAX014 compound was able to counteract HER-2 overexpressing mammary tumors onset and progression in transgenic mice. However, the IP administration was found to induce organ toxicity at doses higher than 2.5 mg/Kg. In this study, we evaluated the effect of intragastric (IG) administration of 20 mg/kg of NAX014 on both safety and anticancer efficacy in HER-2/neu transgenic mice. Furthermore, cancer cell dissemination and migration, tumor cell senescence and immunological changes were examined. Our results demonstrated that IG NAX014 administration delayed the onset of mammary tumors with no negative effects on health and survival. NAX014 reduced HER-2 overexpressing BC cells migration in vitro and the frequency of lung metastasis in HER-2/neu transgenic mice. A statistically significant increase of senescence-associated p16 expression was observed in tumors from NAX014-treated mice, and the induction of cell senescence was observed in HER-2 overexpressing BC cells after in vitro treatment with NAX014. Although NAX014 did not modulate the presence of tumor-infiltrating lymphocytes, the level of circulating TNF-α and VEGF was found to be reduced in NAX014-treated mice. The overall results address the NAX014 compound as potential tool for therapeutic strategies against HER-2 overexpressing breast cancer.


Asunto(s)
Antineoplásicos/uso terapéutico , Alcaloides de Berberina/uso terapéutico , Genes erbB-2 , Neoplasias Mamarias Experimentales/prevención & control , Metástasis de la Neoplasia/prevención & control , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Alcaloides de Berberina/administración & dosificación , Alcaloides de Berberina/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/genética , Ratones , Ratones Transgénicos , Estructura Molecular , Metástasis de la Neoplasia/tratamiento farmacológico , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Ratas , Carga Tumoral/efectos de los fármacos
4.
Methods Mol Biol ; 2279: 35-47, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33683684

RESUMEN

Programmed cell death 1 (PD-1) plays an important role in subsiding immune responses, in promoting self-tolerance through suppressing the activity of T-cells, and in promoting differentiation of regulatory T-cells. One of its ligands, programmed cell death ligand 1 (PD-L1) acts as a checkpoint regulator in immune cells and is also expressed in a wide range of cancer types. Anti-PD therapy modulates immune responses at the tumor site, targets tumor-induced immune defects, and repairs ongoing immune responses. Since drugs that target the PD-1/PD-L1 pathways became available as a cancer treatment, there is need for the use of different antibodies to detect the presence of these proteins in tumoral samples by immunohistochemistry or other assays. Because the detection of these antigens in tumor samples is highly clinically informative for guiding treatment decisions, especially to establish the aptness of a patient to receive anti-PD therapy, it is necessary to have a validation process that guaranties that the test results obtained when using antibodies against these proteins are specific, selective, reproducible, and conducive to quantification of antigen abundance in cancer tissue sections. Here we describe an automated immunohistochemistry staining procedure that can be applied for the validation of multiple anti-PD-L1 antibody clones when used for the staining of formalin-fixed, paraffin-embedded lung cancer tissue sections.


Asunto(s)
Automatización de Laboratorios , Antígeno B7-H1/biosíntesis , Regulación Neoplásica de la Expresión Génica , Inmunohistoquímica , Neoplasias Pulmonares , Proteínas de Neoplasias/biosíntesis , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino
5.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670365

RESUMEN

MicroRNAs (miRNAs) are attractive therapeutic targets and promising candidates as molecular biomarkers for various therapy-resistant tumors. However, the association between miRNAs and drug resistance in melanoma remains to be elucidated. We used an integrative genomic analysis to comprehensively study the miRNA expression profiles of drug-resistant melanoma patients and cell lines. MicroRNA-181a and -181b (miR181a/b) were identified as the most significantly down-regulated miRNAs in resistant melanoma patients and cell lines. Re-establishment of miR-181a/b expression reverses the resistance of melanoma cells to the BRAF inhibitor dabrafenib. Introduction of miR-181 mimics markedly decreases the expression of TFAM in A375 melanoma cells resistant to BRAF inhibitors. Furthermore, melanoma growth was inhibited in A375 and M14 resistant melanoma cells transfected with miR-181a/b mimics, while miR-181a/b depletion enhanced resistance in sensitive cell lines. Collectively, our study demonstrated that miR-181a/b could reverse the resistance to BRAF inhibitors in dabrafenib resistant melanoma cell lines. In addition, miR-181a and -181b are strongly down-regulated in tumor samples from patients before and after the development of resistance to targeted therapies. Finally, melanoma tissues with high miR-181a and -181b expression presented favorable outcomes in terms of Progression Free Survival, suggesting that miR-181 is a clinically relevant candidate for therapeutic development or biomarker-based therapy selection.


Asunto(s)
Proteínas de Unión al ADN/biosíntesis , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Melanoma/metabolismo , MicroARNs/biosíntesis , Proteínas Mitocondriales/biosíntesis , Proteínas de Neoplasias/biosíntesis , ARN Neoplásico/biosíntesis , Factores de Transcripción/biosíntesis , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Femenino , Genómica , Humanos , Masculino , Melanoma/genética , Melanoma/patología , MicroARNs/genética , Proteínas Mitocondriales/genética , Proteínas de Neoplasias/genética , ARN Neoplásico/genética , Factores de Transcripción/genética
6.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670400

RESUMEN

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, with only limited treatment options available. Recently, cancer stem cells (CSCs) have emerged as the potential drivers of tumor progression due to their ability to both self-renew and give rise to differentiated progeny. The CSC state has been linked to the process of epithelial-mesenchymal transition (EMT) and to the highly flexible state of epithelial-mesenchymal plasticity (EMP). We aimed to establish primary breast cancer stem cell (BCSC) cultures isolated from TNBC specimens. These cells grow as tumor spheres under anchorage-independent culture conditions in vitro and reliably form tumors in mice when transplanted in limiting dilutions in vivo. The BCSC xenograft tumors phenocopy the original patient tumor in architecture and gene expression. Analysis of an EMT-related marker profile revealed the concomitant expression of epithelial and mesenchymal markers suggesting an EMP state for BCSCs of TNBC. Furthermore, BCSCs were susceptible to stimulation with the EMT inducer TGF-ß1, resulting in upregulation of mesenchymal genes and enhanced migratory abilities. Overall, primary BCSC cultures are a promising model close to the patient that can be used both in vitro and in vivo to address questions of BCSC biology and evaluate new treatment options for TNBC.


Asunto(s)
Movimiento Celular , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Células Madre Neoplásicas/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Regulación hacia Arriba , Femenino , Humanos , Células MCF-7 , Proteínas de Neoplasias/biosíntesis , Células Madre Neoplásicas/patología , Factor de Crecimiento Transformador beta1/biosíntesis , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología
7.
Int J Mol Sci ; 22(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652578

RESUMEN

Teneurins have been identified in vertebrates as four different genes (TENM1-4), coding for membrane proteins that are mainly involved in embryonic and neuronal development. Genetic studies have correlated them with various diseases, including developmental problems, neurological disorders and congenital general anosmia. There is some evidence to suggest their possible involvement in cancer initiation and progression, and drug resistance. Indeed, mutations, chromosomal alterations and the deregulation of teneurins expression have been associated with several tumor types and patient survival. However, the role of teneurins in cancer-related regulatory networks is not fully understood, as both a tumor-suppressor role and pro-tumoral functions have been proposed, depending on tumor histotype. Here, we summarize and discuss the literature data on teneurins expression and their potential role in different tumor types, while highlighting the possibility of using teneurins as novel molecular diagnostic and prognostic biomarkers and as targets for cancer treatments, such as immunotherapy, in some tumors.


Asunto(s)
Biomarcadores de Tumor/biosíntesis , Regulación Neoplásica de la Expresión Génica , Proteínas de la Membrana/biosíntesis , Proteínas de Neoplasias/biosíntesis , Neoplasias , Humanos , Neoplasias/diagnóstico , Neoplasias/metabolismo , Neoplasias/terapia
8.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33673033

RESUMEN

T-cell clonality testing is integral to the diagnostic work-up of T-cell malignancies; however, current methods lack specificity and sensitivity, which can make the diagnostic process difficult. The recent discovery of a monoclonal antibody (mAb) specific for human TRBC1 will greatly improve the outlook for T-cell malignancy diagnostics. The anti-TRBC1 mAb can be used in flow cytometry immunophenotyping assays to provide a low-cost, robust, and highly specific test that detects clonality of immunophenotypically distinct T-cell populations. Recent studies demonstrate the clinical utility of this approach in several contexts; use of this antibody in appropriately designed flow cytometry panels improves detection of circulating disease in patients with cutaneous T-cell lymphoma, eliminates the need for molecular clonality testing in the context of large granular lymphocyte leukemia, and provides more conclusive results in the context of many other T-cell disorders. It is worth noting that the increased ability to detect discrete clonal T-cell populations means that identification of T-cell clones of uncertain clinical significance (T-CUS) will become more common. This review discusses this new antibody and describes how it defines clonal T-cells. We present and discuss assay design and summarize findings to date about the use of flow cytometry TRBC1 analysis in the field of diagnostics, including lymph node and fluid sample investigations. We also make suggestions about how to apply the assay results in clinical work-ups, including how to interpret and report findings of T-CUS. Finally, we highlight areas that we think will benefit from further research.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Linfoma de Células T , Proteínas de Neoplasias/biosíntesis , Receptores de Antígenos de Linfocitos T alfa-beta/biosíntesis , Linfocitos T/metabolismo , Humanos , Linfoma de Células T/diagnóstico , Linfoma de Células T/metabolismo , Linfoma de Células T/patología , Linfocitos T/patología
9.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33673041

RESUMEN

Primary thrombopoietic mediator thrombopoietin (THPO) is mainly produced by the liver; it may act as a growth factor for hepatic progenitors. Principal angiogenesis inducer vascular endothelial growth factor-A (VEGF-A) is critical for the complex vascular network within the liver architecture. As a cross-regulatory loop between THPO and VEGF-A has been demonstrated in the hematopoietic system, the two growth factors were hypothesized to cooperatively contribute to the progression from liver cirrhosis (LC) to hepatocellular carcinoma (HCC). The mRNA and protein expression levels of THPO, VEGF-A, and their receptors were examined, compared, and correlated in paired cancerous and LC tissues from 26 cirrhosis-related HCC patients, using qRT-PCR and immunohistochemistry. THPO and VEGF-A were alternatively silenced by small interfering RNA (siRNA) in human liver cancer cell lines Huh7 and HepG2. THPO and VEGF-A expressions significantly increased in tumor versus LC tissues. HCC and paired LC cells expressed similar levels of THPO receptor (R), whereas vascular endothelial growth factor receptor (VEGFR) -1 and VEGFR-2 levels were higher in HCC than in corresponding LC tissue samples. A significant linear correlation emerged between THPO and VEGF-A transcripts in HCC and, at the protein level, THPO and THPOR were significantly correlated with VEGF-A in tumor tissues. Both HCC and LC expressed similar levels of gene and protein hypoxia inducible factor (HIF)-1α. Positive cross-regulation occurred with the alternative administration of siRNAs targeting THPO and those targeting VEGF-A in hypoxic liver cancer cell lines. These results suggest THPO and VEGF-A might act as interdependently regulated autocrine and/or paracrine systems for cellular growth in HCC. This might be clinically interesting, since new classes of THPOR agonistic/antagonistic drugs may provide novel therapeutic options to correct the frequent hemostatic abnormality seen in HCC patients.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Cirrosis Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/biosíntesis , Trombopoyetina/biosíntesis , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Anciano , Comunicación Autocrina , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/patología , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Comunicación Paracrina
10.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33673050

RESUMEN

The BIRC (baculoviral IAP repeat-containing; BIRC) family genes encode for Inhibitor of Apoptosis (IAP) proteins. The dysregulation of the expression levels of the genes in question in cancer tissue as compared to normal tissue suggests that the apoptosis process in cancer cells was disturbed, which may be associated with the development and chemoresistance of triple negative breast cancer (TNBC). In our study, we determined the expression level of eight genes from the BIRC family using the Real-Time PCR method in patients with TNBC and compared the obtained results with clinical data. Additionally, using bioinformatics tools (Ualcan and The Breast Cancer Gene-Expression Miner v4.5 (bc-GenExMiner v4.5)), we compared our data with the data in the Cancer Genome Atlas (TCGA) database. We observed diverse expression pattern among the studied genes in breast cancer tissue. Comparing the expression level of the studied genes with the clinical data, we found that in patients diagnosed with breast cancer under the age of 50, the expression levels of all studied genes were higher compared to patients diagnosed after the age of 50. We observed that in patients with invasion of neoplastic cells into lymphatic vessels and fat tissue, the expression levels of BIRC family genes were lower compared to patients in whom these features were not noted. Statistically significant differences in gene expression were also noted in patients classified into three groups depending on the basis of the Scarff-Bloom and Richardson (SBR) Grading System.


Asunto(s)
Bases de Datos de Ácidos Nucleicos , Regulación Neoplásica de la Expresión Génica , Proteínas Inhibidoras de la Apoptosis , Familia de Multigenes , Proteínas de Neoplasias , Neoplasias de la Mama Triple Negativas , Adulto , Anciano , Femenino , Humanos , Proteínas Inhibidoras de la Apoptosis/biosíntesis , Proteínas Inhibidoras de la Apoptosis/genética , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo
11.
BMC Cancer ; 21(1): 213, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33648465

RESUMEN

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common pathology subtype of lung cancer. In recent years, immunotherapy, targeted therapy and chemotherapeutics conferred a certain curative effects. However, the effect and prognosis of LUAD patients are different, and the efficacy of existing LUAD risk prediction models is unsatisfactory. METHODS: The Cancer Genome Atlas (TCGA) LUAD dataset was downloaded. The differentially expressed immune genes (DEIGs) were analyzed with edgeR and DESeq2. The prognostic DEIGs were identified by COX regression. Protein-protein interaction (PPI) network was inferred by STRING using prognostic DEIGs with p value< 0.05. The prognostic model based on DEIGs was established using Lasso regression. Immunohistochemistry was used to assess the expression of FERMT2, FKBP3, SMAD9, GATA2, and ITIH4 in 30 cases of LUAD tissues. RESULTS: In total,1654 DEIGs were identified, of which 436 genes were prognostic. Gene functional enrichment analysis indicated that the DEIGs were involved in inflammatory pathways. We constructed 4 models using DEIGs. Finally, model 4, which was constructed using the 436 DEIGs performed the best in prognostic predictions, the receiver operating characteristic curve (ROC) was 0.824 for 3 years, 0.838 for 5 years, 0.834 for 10 years. High levels of FERMT2, FKBP3 and low levels of SMAD9, GATA2, ITIH4 expression are related to the poor overall survival in LUAD (p < 0.05). The prognostic model based on DEIGs reflected infiltration by immune cells. CONCLUSIONS: In our study, we built an optimal prognostic signature for LUAD using DEIGs and verified the expression of selected genes in LUAD. Our result suggests immune signature can be harnessed to obtain prognostic insights.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Regulación Neoplásica de la Expresión Génica , Inmunidad/genética , Neoplasias Pulmonares/genética , Modelos Biológicos , Proteínas de Neoplasias/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/genética , Conjuntos de Datos como Asunto , Femenino , Ontología de Genes , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/biosíntesis , Pronóstico , Modelos de Riesgos Proporcionales , Curva ROC , Transcriptoma , Microambiente Tumoral/inmunología
12.
Arch Biochem Biophys ; 700: 108774, 2021 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-33548212

RESUMEN

Homoharringtonine (HHT), an approved anti-leukemic alkaloid, has been reported effectively in many types of tumor cells. However, its effect on melanoma cells has not been investigated. And the anti-melanoma mechanism of HHT is still unknown. In this study, we detected the effects of HHT on two melanoma cell lines (A375 and B16F10) and on the A375 xenograft mouse model. HHT significantly inhibited the proliferation of melanoma cells as investigated by the CCK8 method, cell cloning assay, and EdU experiment. HHT induced A375 and B16F10 cells DNA damage, apoptosis, and G2/M cell cycle arrest as proved by TdT-mediated dUTP Nick-End Labeling (TUNEL) and flow cytometry assay. Additionally, the loss of mitochondrial membrane potential in HHT-treated cells were visualized by JC-1 fluorescent staining. For the molecule mechanism study, western blotting results indicated the protein expression levels of ATM, P53, p-P53, p-CHK2, γ-H2AX, PARP, cleaved-PARP, cleaved caspase-3, cleaved caspase-9, Bcl-2, Bax, Aurka, p-Aurka, Plk1, p-Plk1, Cdc25c, CDK1, cyclin B1, and Myt1 were regulated by HHT. And the relative mRNA expression level of Aurka, Plk1, Cdc25c, CDK1, cyclin B1, and Myt1 were ascertained by q-PCR assay. The results in vivo experiment showed that HHT can slow down the growth rate of tumors. At the same time, the protein expression levels in vivo were consistent with that in vitro. Collectively, our study provided evidence that HHT could be considered an effective anti-melanoma agent by inducing DNA damage, apoptosis, and cell cycle arrest.


Asunto(s)
Daño del ADN/efectos de los fármacos , ADN de Neoplasias/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Homoharringtonina/farmacología , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Melanoma Experimental , Animales , Apoptosis , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones , Proteínas de Neoplasias/biosíntesis
13.
Arch Biochem Biophys ; 701: 108795, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33577840

RESUMEN

Ovarian cancer is the most deadly gynaecology related cancer due to its high metastasizing ability. Quercetin is the most abundant flavonoids received increased interest due to its anti-cancer properties. Although the anticancer property of quercetin is very well known, its anti-metastatic effect on metastatic ovarian cancer cells and their underlying molecular mechanism remains to be elucidated. Quercetin treatment at 50 µM and 75 µM concentration inhibit human metastatic ovarian cancer PA-1 cell survival and proliferation via inactivating PI3k/Akt, Ras/Raf pathways and EGFR expression. It also alters the expression of N-cadherin in PA-1 cells. Quercetin also decreases the secretion of gelatinase enzyme, proteolytic activity of MMP-2/-9, and both MMPs gene expression in metastatic ovarian cancer PA-1 cells. In addition to this quercetin inhibits the migration of PA-1 cells. Treatment of quercetin with PA-1 cells also downregulates the tight junctional molecules such as Claudin-4 and Claudin-11 while upregulates the expression of occludin. It is further validated by cell adhesion assay in which quercetin reduces the adhesion of PA-1 ovarian cancer cells. Results suggest that quercetin inhibits cell survival, proliferation, migration, and adhesion which plays crucial role in ovarian cancer metastasis. Hence, it could be a valuable therapeutic drug for the treatment and prevention of metastatic ovarian cancer.


Asunto(s)
Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias Ováricas/metabolismo , Quercetina/farmacocinética , Transducción de Señal/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Metástasis de la Neoplasia , Proteínas de Neoplasias/biosíntesis , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología
14.
DNA Cell Biol ; 40(3): 469-481, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33600260

RESUMEN

Bladder cancer (BC) is a common genitourinary malignancy worldwide. However, the molecular pathogenesis of BC remains unclear. The current study conducted bioinformatic analyses to discover key genes involved in BC progression. A total of 375 differentially expressed genes (DEGs) were screened in the GEO database and The Cancer Genome Atlas (TCGA) database, which were further evaluated by the core level in the protein-protein interaction network. RAC3 (Rac family small GTPase 3), one of the top hub genes, was focused on for its gene expression and prognostic value in BC. Immunohistochemical assays indicated elevated RAC3 levels in BC tissues compared with normal tissues. Overexpression of RAC3 expression was closely associated with poor differentiation (p = 0.035), advanced TNM stage (p = 0.014), lymph metastasis (p = 0.033), and recurrence (p < 0.001). Kaplan-Meier and Cox proportional hazards analyses demonstrated that high RAC3 expression indicated poor survival of BC patients, which could serve as an independent prognostic factor for overall survival (HR = 3.159, p = 0.023) and disease-free survival (HR = 4.633, p = 0.002). Moreover, bioinformatic analyses indicated that RAC3 might be correlated with malignant phenotypes and immune infiltration of BC. Taken together, RAC3 could be a novel prognostic biomarker for BC.


Asunto(s)
Biomarcadores de Tumor/biosíntesis , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/biosíntesis , Neoplasias de la Vejiga Urinaria , Proteínas de Unión al GTP rac/biosíntesis , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Estadificación de Neoplasias , Tasa de Supervivencia , Neoplasias de la Vejiga Urinaria/enzimología , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/mortalidad , Proteínas de Unión al GTP rac/genética
15.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-33540888

RESUMEN

Macrophages are essential immune cells of the innate immune system. They participate in the development and regulation of inflammation. Macrophages play a fundamental role in fighting against bacterial infections by phagocytosis of bacteria, and they also have a specific role in immunomodulation by secreting pro-inflammatory cytokines. In bacterial infection, macrophages decrease the serum iron concentration by removing iron from the blood, acting as one of the most important regulatory cells of iron homeostasis. We examined whether the Gram-positive and Gram-negative cell wall components from various bacterial strains affect the cytokine production and iron transport, storage and utilization of THP-1 monocytes in different ways. We found that S. aureus lipoteichoic acid (LTA) was less effective in activating pro-inflammatory cytokine expression that may related to its effect on fractalkine production. LTA-treated cells increased iron uptake through divalent metal transporter-1, but did not elevate the expression of cytosolic and mitochondrial iron storage proteins, suggesting that the cells maintained iron efflux via the ferroportin iron exporter. E. coli and P. aeruginosa lipopolysaccharides (LPSs) acted similarly on THP-1 cells, but the rates of the alterations of the examined proteins were different. E. coli LPS was more effective in increasing the pro-inflammatory cytokine production, meanwhile it caused less dramatic alterations in iron metabolism. P. aeruginosa LPS-treated cells produced a smaller amount of pro-inflammatory cytokines, but caused remarkable elevation of both cytosolic and mitochondrial iron storage proteins and intracellular iron content compared to E. coli LPS. These results prove that LPS molecules from different bacterial sources alter diverse molecular mechanisms in macrophages that prepossess the outcome of the bacterial infection.


Asunto(s)
Pared Celular/química , Citocinas/metabolismo , Escherichia coli/química , Hierro/metabolismo , Lipopolisacáridos/farmacología , Pseudomonas aeruginosa/química , Staphylococcus aureus/química , Células THP-1/metabolismo , Ácidos Teicoicos/farmacología , Transporte Biológico , Receptor 1 de Quimiocinas CX3C/biosíntesis , Receptor 1 de Quimiocinas CX3C/genética , Quimiocina CX3CL1/metabolismo , Citocinas/biosíntesis , Citosol/metabolismo , Ferritinas/biosíntesis , Ferritinas/genética , Hemo-Oxigenasa 1/biosíntesis , Hemo-Oxigenasa 1/genética , Hepcidinas/biosíntesis , Hepcidinas/genética , Humanos , Mitocondrias/metabolismo , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Oxidorreductasas/biosíntesis , Oxidorreductasas/genética , ARN Mensajero/biosíntesis , ARN Neoplásico/genética , Células THP-1/efectos de los fármacos
16.
BMC Cancer ; 21(1): 200, 2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33637083

RESUMEN

BACKGROUND: Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model. METHODS: We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer. RESULTS: Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes. CONCLUSIONS: Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas de Neoplasias/antagonistas & inhibidores , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Ductal Pancreático/prevención & control , Carcinoma Ductal Pancreático/secundario , Adhesión Celular/efectos de los fármacos , Agregación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Autorrenovación de las Células/efectos de los fármacos , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacología , Sinergismo Farmacológico , Femenino , Proteínas Ligadas a GPI/biosíntesis , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/inmunología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Células Madre Neoplásicas/patología , Tamaño de los Órganos/efectos de los fármacos , Neoplasias Pancreáticas/patología , Neoplasias Peritoneales/prevención & control , Neoplasias Peritoneales/secundario , Peritoneo/efectos de los fármacos , Peritoneo/metabolismo , Peritoneo/patología , Peritonitis/tratamiento farmacológico , Peritonitis/patología
17.
BMC Cancer ; 21(1): 202, 2021 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-33639865

RESUMEN

BACKGROUND: In recent years, emerging studies have demonstrated critical functions and potential clinical applications of long non-coding RNA (lncRNA) in osteosarcoma. To further validate the prognostic value of multiple lncRNAs, we have conducted this updated meta-analysis. METHODS: Literature retrieval was conducted by searching PubMed, Web of Science and the Cochrane Library (last update by October 2, 2019). A meta-analysis was performed to explore association between lncRNAs expression and overall survival (OS) of osteosarcoma patients. Relationships between lncRNAs expression and other clinicopathological features were also analyzed respectively. RESULTS: Overall, 4351 patients from 62 studies were included in this meta-analysis and 25 lncRNAs were identified. Pooled analyses showed that high expression of 14 lncRNAs connoted worse OS, while two lncRNAs were associated with positive outcome. Further, analysis toward osteosarcoma clinicopathologic features demonstrated that overexpression of TUG1 and XIST indicated poor clinical parameters of patients. CONCLUSIONS: This meta-analysis has elucidated the prognostic potential of 16 lncRNAs in human osteosarcoma. Evidently, desperate expression and functional targets of these lncRNAs offer new approaches for prognosis and therapy of osteosarcoma.


Asunto(s)
Neoplasias Óseas/sangre , Osteosarcoma/sangre , ARN Largo no Codificante/sangre , ARN Neoplásico/sangre , Biomarcadores de Tumor , Neoplasias Óseas/genética , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Osteosarcoma/genética , Osteosarcoma/mortalidad , Osteosarcoma/patología , Pronóstico , Sesgo de Publicación
18.
Mol Med Rep ; 23(4)2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33537819

RESUMEN

Hyperthermia is one of the most widely employed adjuvant treatments for cancer, especially for hyperthermic intraperitoneal chemotherapy, and has few side effects. Gastric cancer has various hyperthermia sensitivities, but the exact molecular mechanisms remain to be elucidated. In the present study, western blotting was performed to detect differential expression of proteins that have been reported to be upregulated in gastric cancer. Following knockdown of these proteins, apoptosis was measured by Annexin V­FITC/propidium iodide (PI) double staining and hyperthermia treatment was applied. To evaluate the effect of cyclin­dependent kinase 6 (CDK6) on hyperthermia­induced apoptosis, CDK6 was knocked down or inhibited by the addition of a specific inhibitor and subsequent PI staining and cell proliferation, migration and invasion assays were performed. Hyperthermia­induced protein kinase B (AKT) expression and phosphorylation inhibition were detected. As demonstrated in the present study, the hyperthermia­induced proteins kinesin family member 11 (KIF11), cyclin­dependent kinase 6 (CDK6), stromal antigen 2, NIMA­related kinase 2 and karyopherin subunit α 4 were highly expressed in gastric cancer cells, including SH­10­TC and HGC­27 cells. Knockdown of KIF11 significantly increased apoptosis without hyperthermia treatment and CDK6 significantly increased hyperthermia­induced apoptosis, prompting the present study to focus on CDK6. It was further confirmed that CDK6 activity was critical for decreasing hyperthermia­induced apoptosis and for cell proliferation. Hyperthermia­induced AKT expression and phosphorylation inhibition is potentially the main cause of CDK6 transcriptional upregulation. Taken together, these findings demonstrated that CDK6 is upregulated via hyperthermia­induced AKT inhibition and subsequently protected gastric cancer cells from hyperthermia­induced apoptosis, indicating that it is a potential therapeutic target to sensitize gastric cancer cells to hyperthermia­based therapy.


Asunto(s)
Quinasa 6 Dependiente de la Ciclina/biosíntesis , Regulación Neoplásica de la Expresión Génica , Hipertermia Inducida , Proteínas de Neoplasias/biosíntesis , Neoplasias Gástricas/metabolismo , Transcripción Genética , Regulación hacia Arriba , Línea Celular Tumoral , Quinasa 6 Dependiente de la Ciclina/genética , Humanos , Proteínas de Neoplasias/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia
19.
Genet Test Mol Biomarkers ; 25(1): 68-78, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33470885

RESUMEN

Aims: We analyzed and compared the gene expression profiles (GSE92763) from normal melanocytes with malignant melanoma cell lines to identify genes that were differentially expressed that could serve as potential biomarkers for melanoma diagnosis. Materials and Methods: Gene expression profiles from the GSE92763 dataset were downloaded from the Gene Expression Omnibus (GEO) database. By comparing normal human melanocytes with multiple melanoma cell lines we identified 127 differentially expressed genes whose expression was altered. These data were used to identify hub genes associated with protein-protein interaction networks using Cytoscape software. To explore the biological functions of the aforementioned hub genes, we utilized the clusterProfiler package in R studio to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. We then used the Gene Expression Profiling Interactive Analysis (GEPIA) website to determine the association of these hub genes with overall survival (OS). In addition, we utilized the Oncomine and Cancer Cell Line Encyclopedia (CCLE) databases to further analyze and compare the expression of these key genes associated with melanoma with other tumor types. Results: The hub genes included three upregulated and seven downregulated genes, which were linked with extracellular junctions, migration, paracrine and proliferation functions based on GO. In addition, we performed a confirmatory analysis of the hub genes using The Cancer Genome Atlas (TCGA) database. This analysis revealed that the expression of the Fibulin 1 (FBLN1; gene ID: 2192) gene was significantly downregulated in melanomas, and that its expression level in melanoma patients was significantly associated with OS with high expressors having better OS (log-rank p = 0.0034, hazard ratio = 1.5, p = 0.0036). We further analyzed the expression of FBLN1 in melanoma using the TCGA and Oncomine databases, and confirmed that FBLN1 is expressed at lower levels than in other cells (p = 2.03E-15, t = -15.586). FBLN1 has extremely high DNA copy number and low messenger RNA expression in melanoma cell lines according to the CCLE analysis. Conclusion: These results suggest that FBLN1 expression may be utilized as a biomarker and essential prognostic factor for melanoma; as well as provide an important theoretical basis for the development of melanoma treatments.


Asunto(s)
Biomarcadores de Tumor , Proteínas de Unión al Calcio , Bases de Datos de Ácidos Nucleicos , Regulación Neoplásica de la Expresión Génica , Melanoma , MicroARNs , Proteínas de Neoplasias , ARN Neoplásico , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Proteínas de Unión al Calcio/biosíntesis , Proteínas de Unión al Calcio/genética , Perfilación de la Expresión Génica , Ontología de Genes , Humanos , Melanoma/genética , Melanoma/metabolismo , MicroARNs/biosíntesis , MicroARNs/genética , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética
20.
Genet Test Mol Biomarkers ; 25(1): 1-11, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33470887

RESUMEN

Objective: The aim of this study was to use bioinformatic analyses to identify key genes and pathways driving gastric cancer (GC). Materials and Methods: The gene expression profiles, from human gastric tissue samples were downloaded from the Gene Expression Omnibus (GSE)29272 dataset. These data revealed 284 differentially expressed genes (DEGs) that included a group upregulated in cancer tissues (n = 142) and another group that were downregulated in cancer tissues. (n = 142). These DEGs were identified using the GEO2R. We used multiple online analysis tools, including, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction networks, gene expression profiling interactive analysis (GEPIA), and the cBio Cancer Genomics Portal (cBioportal) database. Next, we identified the most significant DEGs using the Kaplan-Meier plotter (KM-plotter) database. Multiple bioinformatic platforms were used to identify candidate prognostic marker genes. We then analyzed freshly frozen GC tissues for the expression of these marker genes to validate the informatic findings. Results: We identified three DEGs related to overall survival from our analyses of the GEO data. Next, we analyzed these three DEGs in GEPIA and the cBioportal database and found that the biglycan (BGN) gene was related to invasion and metastases of GCs. This finding of differential gene expression was confirmed in a separate laboratory analysis of normal and GC tissues. In this analysis we found that high levels of BGN expression were correlated with GC clinicopathological characteristics, including microvascular tumor thrombus (p = 0.018), lymph node metastases (p = 0.013), and vessel invasion (p = 0.004). Conclusions: BGN expression levels appear to be an independent prognostic factor for predicting the survival times of GC patients.


Asunto(s)
Biomarcadores de Tumor , Bases de Datos Genéticas , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias , Mapas de Interacción de Proteínas , Neoplasias Gástricas , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Biología Computacional , Perfilación de la Expresión Génica , Humanos , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
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