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1.
Medicine (Baltimore) ; 100(14): e25270, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33832090

RESUMEN

ABSTRACT: Del-1 has been linked to the pathogenesis of various cancers, including breast cancer. However, the regulation of Del-1 expression remains unclear. We previously reported the interaction between microRNA-137 (miR-137) and the Del-1 gene. In this study, we investigated miR-496 and miR-137 as regulators of Del-1 expression in triple negative breast cancer (TNBC). Del-1 mRNA and miR-496 were measured by quantitative PCR in breast cancer cells (MDA-MB-231, MCF7, SK-BR3, and T-47D) and tissues from 30 patients with TNBC. The effects of miR-496 on cell proliferation, migration, and invasion were determined with MTT, wound healing, and Matrigel transwell assays, respectively. In MDA-MB-231 cells, miR-496 levels were remarkably low and Del-1 mRNA levels were higher than in other breast cancer cell lines. Luciferase reporter assays revealed that miR-496 binds the 3'-UTR of Del-1 and Del-1 expression is downregulated by miR-496 mimics. Furthermore, miR-496 inhibited the proliferation, migration, and invasion of MDA-MB-231 cells. The effects of miR-496 on cell proliferation were additive with those of miR-137, another miRNA that regulates Del-1 expression. Moreover, in the 30 TNBC specimens, miR-496 was downregulated (P < .005) and the levels of Del-1 in the plasma were significantly elevated as compared with in normal controls (P = .0142). The Cancer Genome Atlas (TCGA) data showed the correlation of miR-496 expression with better overall survival in patients with early TNBC. In in silico and in vitro analyses, we showed that Del-1 is a target of miR-496 in TNBC and thereby affects cancer progression. Our findings suggest that miR-496 and miR-137 additively target Del-1 and act as modulating factors in TNBC. They are potentially new biomarkers for patients with TNBC.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , MicroARNs/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Proteínas de Unión al Calcio , Moléculas de Adhesión Celular , Línea Celular Tumoral , Proliferación Celular , Regulación hacia Abajo , Femenino , Humanos , MicroARNs/genética , Invasividad Neoplásica/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología
2.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33804289

RESUMEN

The K+-sparing diuretic amiloride shows off-target anti-cancer effects in multiple rodent models. These effects arise from the inhibition of two distinct cancer targets: the trypsin-like serine protease urokinase-type plasminogen activator (uPA), a cell-surface mediator of matrix degradation and tumor cell invasiveness, and the sodium-hydrogen exchanger isoform-1 (NHE1), a central regulator of transmembrane pH that supports carcinogenic progression. In this study, we co-screened our library of 5- and 6-substituted amilorides against these two targets, aiming to identify single-target selective and dual-targeting inhibitors for use as complementary pharmacological probes. Closely related analogs substituted at the 6-position with pyrimidines were identified as dual-targeting (pyrimidine 24 uPA IC50 = 175 nM, NHE1 IC50 = 266 nM, uPA selectivity ratio = 1.5) and uPA-selective (methoxypyrimidine 26 uPA IC50 = 86 nM, NHE1 IC50 = 12,290 nM, uPA selectivity ratio = 143) inhibitors, while high NHE1 potency and selectivity was seen with 5-morpholino (29 NHE1 IC50 = 129 nM, uPA IC50 = 10,949 nM; NHE1 selectivity ratio = 85) and 5-(1,4-oxazepine) (30 NHE1 IC50 = 85 nM, uPA IC50 = 5715 nM; NHE1 selectivity ratio = 67) analogs. Together, these amilorides comprise a new toolkit of chemotype-matched, non-cytotoxic probes for dissecting the pharmacological effects of selective uPA and NHE1 inhibition versus dual-uPA/NHE1 inhibition.


Asunto(s)
Amilorida/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Intercambiador 1 de Sodio-Hidrógeno/genética , Activador de Plasminógeno de Tipo Uroquinasa/genética , Amilorida/síntesis química , Amilorida/química , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Diuréticos/síntesis química , Diuréticos/química , Diuréticos/farmacología , Femenino , Humanos , Modelos Moleculares , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Intercambiador 1 de Sodio-Hidrógeno/antagonistas & inhibidores , Relación Estructura-Actividad , Activador de Plasminógeno de Tipo Uroquinasa/antagonistas & inhibidores
3.
Int Braz J Urol ; 47(4): 803-818, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33848073

RESUMEN

BACKGROUND: Guideline-based best practice treatment for muscle invasive bladder cancer (MIBC) involves neoadjuvant chemotherapy followed by radical cystectomy (NACRC). Prior studies have shown that a minority of patients receive NACRC and older age and renal function are drivers of non-receipt of NACRC. This study investigates treatment rates and factors associated with not receiving NACRC in MIBC patients with lower comorbidity status most likely to be candidates for NACRC. MATERIALS AND METHODS: Retrospective United States National Cancer Database analysis from 2006 to 2015 of MIBC patients with Charlson comorbidity index (CCI) of zero. Analysis of NACRC treatment trends in higher CCI patients was also performed. RESULTS: 15.561 MIBC patients met inclusion criteria. 1.507 (9.7%) received NACRC within 9 months of diagnosis. NACRC increased over time (15.0% in 2015 compared to 3.6% in 2006). Higher NACRC was noted in females, cT3 or cT4 cancer, later year of diagnosis, and academic facility treatment. Lower utilization was noted for blacks and NACRC decreased with increasing age and CCI. Only 16.9% of patients aged 23-62 in the lowest age quartile with muscle invasive bladder cancer and CCI of 0 received NACRC. CONCLUSIONS: Although utilization is increasing, receipt of NACRC remains low even in populations most likely to be candidates. Further study should continue to elucidate barriers to utilization of NACRC.


Asunto(s)
Neoplasias de la Vejiga Urinaria , Adulto , Anciano , Comorbilidad , Cistectomía , Femenino , Humanos , Persona de Mediana Edad , Músculos , Terapia Neoadyuvante , Invasividad Neoplásica , Estudios Retrospectivos , Estados Unidos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/cirugía , Adulto Joven
4.
World J Surg Oncol ; 19(1): 125, 2021 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-33866973

RESUMEN

BACKGROUND: Lymphovascular invasion (LVI) is defined as the presence of cancer cells in lymphatics or blood vessels. This study aimed to evaluate the prognostic value of LVI in stage II colorectal cancer (CRC) patients with inadequate examination of lymph nodes (ELNs) and further combined LVI with the TNM staging system to determine the predictive efficacy for CRC prognosis. Adjuvant chemotherapy (ACT) was then evaluated for stage II CRC patients with LVI positivity (LVI+). METHODS: In order to avoid the effects of different ACT regimens, among 409 stage II patients, we chose 121 patients who received FOLFOX regimen and the 144 patients who did not receive ACT as the object of study. LVI was examined by hematoxylin-eosin (HE) staining. Kaplan-Meier analysis followed by a log-rank test was used to analyze survival rates. Univariate and multivariate analyses were performed using a Cox proportional hazards model. Harrell's concordance index (C-index) was used to evaluate the accuracy of different systems in predicting prognosis. RESULTS: The LVI+ status was significantly associated with pT stage, degree of differentiation, tumor stage, serum CEA and CA19-9 levels, perineural invasion (PNI), tumor budding (TB), and KRAS status. The 5-year overall survival (OS) rate of stage II patients with < 12 ELNs and LVI+ was less than stage IIIA. Multivariate analyses showed that LVI, pT-stage, serum CEA and CA19-9 levels, PNI, TB, and KRAS status were significant prognostic factors for stage II patients with < 12 ELNs. The 8th TNM staging system combined with LVI showed a higher C-index than the 8th TNM staging system alone (C-index, 0.895 vs. 0.833). Among patients with LVI+, the ACT group had a significantly higher 5-year OS and 5-year disease-free survival (DFS) than the surgery alone (SA) group (5-year OS, 66.7% vs. 40.9%, P = 0.004; 5-year DFS, 64.1% vs. 36.3%, P = 0.002). CONCLUSIONS: LVI is an independent prognostic risk factor for stage II CRC patients. Combining LVI with the 8th TNM staging system improved the predictive accuracy for CRC prognosis. ACT in stage II CRC patients with LVI+ is beneficial for survival.


Asunto(s)
Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Endotelio Vascular/patología , Invasividad Neoplásica/patología , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Neoplasias Colorrectales/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia
5.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-33803452

RESUMEN

Apoptosis is the main mechanism by which multicellular organisms eliminate damaged or unwanted cells. To regulate this process, a balance between pro-survival and pro-apoptotic proteins is necessary in order to avoid impaired apoptosis, which is the cause of several pathologies, including cancer. Among the anti-apoptotic proteins, Bcl-xL exhibits a high conformational flexibility, whose regulation is strictly controlled by alternative splicing and post-transcriptional regulation mediated by transcription factors or microRNAs. It shows relevant functions in different forms of cancer, including melanoma. In melanoma, Bcl-xL contributes to both canonical roles, such as pro-survival, protection from apoptosis and induction of drug resistance, and non-canonical functions, including promotion of cell migration and invasion, and angiogenesis. Growing evidence indicates that Bcl-xL inhibition can be helpful for cancer patients, but at present, effective and safe therapies targeting Bcl-xL are lacking due to toxicity to platelets. In this review, we summarized findings describing the mechanisms of Bcl-xL regulation, and the role that Bcl-xL plays in melanoma pathobiology and response to therapy. From these findings, it emerged that even if Bcl-xL plays a crucial role in melanoma pathobiology, we need further studies aimed at evaluating the involvement of Bcl-xL and other members of the Bcl-2 family in the progression of melanoma and at identifying new non-toxic Bcl-xL inhibitors.


Asunto(s)
Apoptosis , Resistencia a Antineoplásicos , Melanoma/irrigación sanguínea , Melanoma/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Proteína bcl-X/metabolismo , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , MicroARNs/metabolismo , Invasividad Neoplásica , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , ARN Neoplásico/metabolismo
6.
Medicine (Baltimore) ; 100(14): e25415, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33832139

RESUMEN

BACKGROUND: Circular RNAs (circRNAs) regulate multiple pathways during lung cancer pathogenesis. Apart from functional significance, many circRNAs have been shown to be associated with clinicopathological characteristics and predict lung cancer prognosis. Our aim is to summarize the expanding knowledge of clinical roles of circRNAs in lung cancer. METHODS: A thorough search of literature was conducted to identify articles about the correlation between circRNA expression and its prognostic and clinicopathological values. Biological mechanisms were summarized. RESULTS: This study included 35 original articles and 32 circRNAs with prognostic roles for lung cancer. Increased expression of 25 circRNAs and decreased expression of 7 circRNAs predicted poor prognosis. For non-small cell lung cancer, changes of circRNAs were correlated with tumor size, lymph node metastasis, distant metastasis, tumor node metastasis (TNM) stage, and differentiation, indicating the major function of circRNAs is to promote lung cancer invasion and migration. Particularly, meta-analysis of ciRS-7, hsa_circ_0020123, hsa_circ_0067934 showed increase of the 3 circRNAs was associated with positive lymph node metastasis. Increase of ciRS-7 and hsa_circ_0067934 was also related with advanced TNM stage. The biological effects depend on the general function of circRNA as microRNA sponge. CONCLUSIONS: CircRNAs have the potential to function as prognostic markers and are associated with lung cancer progression and metastasis.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Pulmonares/diagnóstico , ARN Circular/metabolismo , Progresión de la Enfermedad , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Invasividad Neoplásica , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico
7.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33806300

RESUMEN

Connexin- and pannexin (Panx)-formed hemichannels (HCs) and gap junctions (GJs) operate an interaction with the extracellular matrix and GJ intercellular communication (GJIC), and on account of this they are involved in cancer onset and progression towards invasiveness and metastatization. When we deal with cancer, it is not correct to omit the immune system, as well as neglecting its role in resisting or succumbing to formation and progression of incipient neoplasia until the formation of micrometastasis, nevertheless what really occurs in the tumor microenvironment (TME), which are the main players and which are the tumor or body allies, is still unclear. The goal of this article is to discuss how the pivotal players act, which can enhance or contrast cancer progression during two important process: "Activating Invasion and Metastasis" and the "Avoiding Immune Destruction", with a particular emphasis on the interplay among GJIC, Panx-HCs, and the purinergic system in the TME without disregarding the inflammasome and cytokines thereof derived. In particular, the complex and contrasting roles of Panx1/P2X7R signalosome in tumor facilitation and/or inhibition is discussed in regard to the early/late phases of the carcinogenesis. Finally, considering this complex interplay in the TME between cancer cells, stromal cells, immune cells, and focusing on their means of communication, we should be capable of revealing harmful messages that help the cancer growth and transform them in body allies, thus designing novel therapeutic strategies to fight cancer in a personalized manner.


Asunto(s)
Comunicación Celular/fisiología , Neoplasias/terapia , Microambiente Tumoral/fisiología , Adenosina Trifosfato/metabolismo , Animales , Comunicación Celular/inmunología , Conexinas/fisiología , Citocinas/inmunología , Transición Epitelial-Mesenquimal/fisiología , Uniones Comunicantes/fisiología , Humanos , Inmunidad Innata , Inflamasomas/inmunología , Modelos Biológicos , Invasividad Neoplásica/patología , Invasividad Neoplásica/fisiopatología , Metástasis de la Neoplasia/patología , Metástasis de la Neoplasia/fisiopatología , Neoplasias/patología , Neoplasias/fisiopatología , Escape del Tumor , Microambiente Tumoral/inmunología
8.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33806361

RESUMEN

Oral cancers constitute the majority of head and neck tumors, with a relatively high incidence and poor survival rate in developing countries. While the five-year survival rates of the oral cancer patients have increased to 65%, the overall survival for advanced stages has been at 27% for the past ten years, emphasizing the necessity for further understanding the etiology of the disease, diagnosis, and formulating possible novel treatment regimens. MicroRNAs (miRNAs), a family of small non-coding RNA, have emerged as master modulators of gene expression in various cellular and biological process. Aberrant expression of these dynamic molecules has been associated with many human diseases, including oral cancers. The deregulated miRNAs have been shown to control various oncogenic processes, including sustaining proliferative signaling, evading growth suppressors, resisting cell death activating invasion and metastasis, and inducing angiogenesis. Hence, the aberrant expression of miRNAs associated with oral cancers, makes them potential candidates for the investigation of functional markers, which will aid in the differential diagnosis, prognosis, and development of novel therapeutic regimens. This review presents a holistic insight into our understanding of the role of miRNAs in regulating various hallmarks of oral tumorigenesis.


Asunto(s)
MicroARNs/genética , Neoplasias de la Boca/etiología , Neoplasias de la Boca/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/etiología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Apoptosis/genética , Biomarcadores de Tumor/genética , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/biosíntesis , Neoplasias de la Boca/patología , Invasividad Neoplásica/genética , Metástasis de la Neoplasia/genética , Oncogenes , Tolerancia a Radiación/genética , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello/patología
9.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(3): 447-452, 2021 Mar 25.
Artículo en Chino | MEDLINE | ID: mdl-33849838

RESUMEN

OBJECTIVE: To investigate the effect of speckle-type POZ protein (SPOP) on proliferation, apoptosis, migration and invasion of renal cell carcinoma (RCC) and explore the potential mechanisms. OBJECTIVE: Renal carcinoma cell lines (786-O, A704, and Caki-2) cultured in vitro were transfected with a SPOP-overexpressing plasmid, and the changes in proliferation of the cells were detected using colony formation and MTT assay; TUNEL assay was used to assess apoptosis of the cells. The changes in migration and invasion abilities of the cells were examined using wound healing assay and Transwell assay. The mRNA and protein levels of SPOP and c-Jun in the transfected cells were measured using real-time PCR and Western blotting. OBJECTIVE: SPOP over-expression obviously promoted the proliferation, migration and invasion of 786-O, A704 and Caki-2 cells (P < 0.05). Compared with the control cells, 786-o and Caki-2 cells over-expressing SPOP exhibited significantly lowered apoptosis rates (P < 0.05). The results of real-time PCR demonstrated that the transfected cells did not show obvious changes in the mRNA level of c-Jun, but the protein expressions of SPOP and c-jun increased significantly as shown by Western blotting (P < 0.05). OBJECTIVE: SPOP can promote proliferation, migration, and invasion and suppress apoptosis of renal carcinoma cells possibly by promoting the expression of c-Jun.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Apoptosis , Carcinoma de Células Renales/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/genética , Invasividad Neoplásica , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-jun , Proteínas Represoras/genética , Proteínas Represoras/metabolismo
10.
Pan Afr Med J ; 38: 85, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33889251

RESUMEN

Introduction: this study aimed to determine the prevalence of receptor status and molecular subtypes in women with breast cancer treated at Potchefstroom Regional Hospital, South Africa and to analyze the association of molecular subtypes with some clinicopathologic characteristics of the tumor. Methods: the study population for this cross-sectional study consisted of 116 women with primary invasive breast cancer, treated at the hospital from 1st January 2012 to 31st December 2018. Molecular subtypes were classified by immunohistochemical surrogates as luminal A (estrogen receptor (ER) positive and/or progesterone receptor (PR) positive, HER2-; Ki-67 <30%), luminal B HER2- (ER+ and/or PR+, HER2-; Ki-67 ≥30%), luminal B HER2+ (ER+ and/or PR+, HER2+; any Ki-67), HER2 enriched (ER- and PR-, HER2+; any Ki-67), or triple-negative (ER-, PR-, HER2-, any Ki-67). Results: the proportions of breast cancer receptor status of ER+, PR+ and HER2-, were 71.6%, 64.7% and 75.9%, respectively. The molecular subtypes of 29.3% of patients were luminal A-type, 24.1% were luminal B HER2-, 22.4% were triple-negative, 18.1% were luminal B HER2+ and 6% were HER2-enriched. Molecular subtypes were significantly associated with tumor grade (p <0.001; Cramér's V=0.337), but independent of age (p=0.847), menopausal status (p=0.690), histology type (p=0.316), cancer stage (p=0.819), lymph node status (p=0.362), or tumor size (p=0.255). Conclusion: the study has revealed that most of the breast cancer in our setting was receptor-positive; approximately one-quarter were triple-negative. Furthermore, the study showed that luminal type A and B are the preponderant molecular subtypes. Molecular subtypes were associated with tumor grade but independent of age and menopausal status. The current study may assist in guiding the therapeutic strategy for patients with breast cancer in the Potchefstroom hospital catchment area.


Asunto(s)
Neoplasias de la Mama/patología , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Estudios Transversales , Femenino , Humanos , Antígeno Ki-67/metabolismo , Menopausia , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Receptor ErbB-2/metabolismo , Receptores Estrogénicos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Sudáfrica
11.
Anticancer Res ; 41(4): 1733-1744, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813377

RESUMEN

BACKGROUND/AIM: We sought to identify the mechanisms of perineural invasion in pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: We utilized in vitro cancer cell-nerve co-culture models comprising human PDAC cell lines (MIA Paca2 and PANC-1) and a dorsal root ganglion (DRG) isolated from neonatal mice. We compared gene expression profiles between cell lines with/without DRG conditioned medium (DRG-CM) using RNA-sequencing (RNA-seq). RESULTS: Migration, invasion, and neurotropism were significantly enhanced in MIA Paca2 but not in PANC-1 cells co-cultured with DRGs. Among 285 genes which showed significant differences in expression levels between cell lines in RNA-seq, we focused on Ephrin receptor A4 (EPHA4), which was upregulated in MIA Paca2 cells treated with DRG-CM. The abilities of migration, invasion, and neurotropism enhanced by DRG co-culture were abolished when EPHA4 was knocked down by siRNA in MIA Paca2 cells. CONCLUSION: EPHA4 can be a potential target gene to regulate perineural invasion in PDAC cells.


Asunto(s)
Carcinoma Ductal Pancreático/metabolismo , Movimiento Celular , Ganglios Espinales/metabolismo , Neoplasias Pancreáticas/metabolismo , Comunicación Paracrina , Receptor EphA4/metabolismo , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Técnicas de Cocultivo , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Endogámicos ICR , Invasividad Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Receptor EphA4/genética , Transducción de Señal
12.
Anticancer Res ; 41(4): 1821-1830, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813387

RESUMEN

BACKGROUND/AIM: Lewis y is expressed in oral squamous cell carcinoma (OSCC) cells and tumors. Previously, we reported that Lewis y was not expressed in invasion areas, and attenuation of proliferation and invasion in OSCC cells was caused by over-expression of Lewis y. However, the roles of Lewis y in the attenuation of malignant properties have not been clarified. In this study, we investigated the roles of Lewis y in OSCC. MATERIALS AND METHODS: The levels of Lewis y on EGFR and the phosphorylation levels of EGFR in OSCC cells were analyzed by immunoprecipitation and western blot. EGFR cross-linking and binding kinetics of EGF were performed. RESULTS: Upon EGF stimulation, phosphorylation and dimer formation of EGFR were more prominent in Lewis y- cells. EGF binding kinetics showed reduced binding sites in Lewis y+ cells. CONCLUSION: Lewis y reduced EGF binding to EGFR, leading to suppression of malignant properties through suppression of EGF signaling.


Asunto(s)
Factor de Crecimiento Epidérmico/metabolismo , Antígenos del Grupo Sanguíneo de Lewis/metabolismo , Neoplasias de la Boca/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Sitios de Unión , Adhesión Celular , Línea Celular Tumoral , Movimiento Celular , Forma de la Célula , Receptores ErbB/metabolismo , Humanos , Cinética , Neoplasias de la Boca/patología , Invasividad Neoplásica , Fosforilación , Unión Proteica , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello/patología
13.
Anticancer Res ; 41(4): 1859-1870, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813391

RESUMEN

BACKGROUND/AIM: Demethoxycurcumin (DMC), one of the derivatives of curcumin, has been shown to induce apoptotic cell death in many human cancer cell lines. However, there is no available information on whether DMC inhibits metastatic activity in human glioblastoma cancer cells in vitro. MATERIALS AND METHODS: DMC at 1.0-3.0 µM significantly decreased the proliferation of GBM 8401 cells; thus, we used 2.0 µM for further investigation regarding anti-metastatic activity in human glioblastoma GBM 8401 cells. RESULTS: The internalized amount of DMC has reached the highest level in GBM 8401 cells after 3 h treatment. Wound healing assay was used to determine cell mobility and results indicated that DMC suppressed cell movement of GBM 8401 cells. The transwell chamber assays were used for measuring cell migration and invasion and results indicated that DMC suppressed cell migration and invasion in GBM 8401 cells. Gelatin zymography assay was used to examine gelatinolytic activity (MMP-2) in conditioned media of GBM 8401 cells treated by DMC and results demonstrated that DMC significantly reduced MMP-2 activity. Western blotting showed that DMC reduced the levels of p-EGFR(Tyr1068), GRB2, Sos1, p-Raf, MEK, p-ERK1/2, PI3K, p-Akt/PKBα(Thr308), p-PDK1, NF-κB, TIMP-1, MMP-9, MMP-2, GSK3α/ß, ß-catenin, N-cadherin, and vimentin, but it elevated Ras and E-cadherin at 24 h treatment. CONCLUSION: DMC inhibited cancer cell migration and invasion through inhibition of PI3K/Akt and NF-κB signaling pathways in GBM 8401 cells. We suggest that DMC may be used as a novel anti-metastasis agent for the treatment of human glioblastoma cancer in the future.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Diarilheptanoides/farmacología , Glioblastoma/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Glioblastoma/enzimología , Glioblastoma/patología , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , FN-kappa B/metabolismo , Invasividad Neoplásica , Transducción de Señal , beta Catenina/metabolismo
14.
Anticancer Res ; 41(4): 2141-2145, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813425

RESUMEN

BACKGROUND/AIM: We compared the outcome of docetaxel, cisplatin, and 5-fluorouracil as combination chemoradiotherapy (DCF-RT) for unresectable locally advanced thoracic esophageal cancer (EC) with that of cisplatin (CDDP) and 5-fluorouracil (5-FU) as combination chemoradiotherapy (CF-RT) in clinical settings. PATIENTS AND METHODS: Seventy-three patients with unresectable locally advanced thoracic EC were included in this study. CF (n=38) consisted of intravenous CDDP at 70 mg/m2 (day 1) and 5-FU at 700 mg/m2 (days 1 to 4), repeated every four weeks for two cycles. DCF (n=35) consisted of intravenous docetaxel at 50 mg/m2 (day 1), CDDP at 60 mg/m2 (day 1), and 5-FU at 600 mg/m2 (days 1 to 4), repeated every four weeks for two cycles. Patients were irradiated with 60 Gy in 30 fractions. RESULTS: The overall complete response (CR) rate of DCF-RT was significantly higher than that of CF-RT (36.7% vs. 3.7%, p=0.003). The 3-year overall survival (OS) rate of DCF-RT was significantly higher than that of CF-RT (32.8% vs. 8.5%, p<0.001). CONCLUSION: DCF-RT demonstrated a higher CR rate and OS for unresectable locally advanced thoracic EC than CF-RT.


Asunto(s)
Quimioradioterapia , Cisplatino/administración & dosificación , Docetaxel/administración & dosificación , Neoplasias Esofágicas/terapia , Fluorouracilo/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Cisplatino/efectos adversos , Progresión de la Enfermedad , Docetaxel/efectos adversos , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Femenino , Fluorouracilo/efectos adversos , Humanos , Japón/epidemiología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Radioterapia de Intensidad Modulada/métodos , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento
15.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(2): 326-333, 2021 Mar.
Artículo en Chino | MEDLINE | ID: mdl-33829710

RESUMEN

Objective: To explore the best treatment plan of intravesical instillation for patients with non-muscular invasive bladder cancer (NMIBC), to explore recurrence-related clinicopathological factors after intravesical instillation, and to evaluate the value of the prognosis and prediction models currently used for NMIBC patients. Methods: Starting from 2016, patients who underwent transurethral resection of bladder tumor (TURBT) in our hospital and who received post-surgery diagnosis of having intermediate or high risks for NMIBC were enrolled in the study. They were randomly assigned to different group sat a ratio of 2∶2∶1 for receiving intravesical instillation therapy of Bacillus Calmette-Guérin (BCG) for 19 times, BCG for 15 times, and epirubicin (EPI) for 18 times. The clinicopathological data of the patients were recorded before, during and after instillation therapy, and survival curves were drawn to evaluate the effects of the three regimens, using recurrence-free survival as the endpoint. Clinicopathological data were analyzed to study the associations between various factors and post-instillation recurrence. The consistency index (c-index) was used to evaluate the predictive accuracy of the scoring model of the Spanish Urological Club for Oncological Treatment (CUETO) and the risk tables of European Organization for Research and Treatment of Cancer (EORTC). Results: A total of 93 NMIBC patients (35 in the 19-time BCG group, 37 in the 15-time BCG group, and 21 in the EPI group) were included, with a median follow-up time of 33.46 months. Twenty-two patients experienced tumor recurrence and eight, tumor progression. The survival curve showed that the BCG group had better recurrence-free survival than the EPI group ( P=0.002), while the difference in recurrence-free survival between 19-time BCG and 15-time BCG groups was not statistically significant. Higher general complication rate was seen in the BCG groups compared with the EPI group (84.7% vs. 61.9%, P=0.022), but there was no grade 3-5 adverse events in any group. The c-index of CUETO scoring model and EORTC risk tables was higher than that of the prediction based solely on T stage, nuclear grade, or EAU risk stratification. In addition, the c-index in the BCG group was higher than that in the whole cohort. Conclusion: Among the subjects of this study, the recurrence rate of bladder cancer in the intravesical BCG instillation groups was lower than that of the epirubicin group. EORTC risk tables and CUETO scoring model exhibited higher predictive accuracies in BCG-treated patients than its performance for the whole NMIBC cohort.


Asunto(s)
Neoplasias de la Vejiga Urinaria , Adyuvantes Inmunológicos/uso terapéutico , Administración Intravesical , Vacuna BCG/uso terapéutico , Humanos , Invasividad Neoplásica , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico
16.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33803949

RESUMEN

Invasive urothelial carcinomas of the bladder (UCB) characteristically show a loss of differentiation markers. The transcription factor Grainyhead-like 3 (GRHL3) plays an important role in the development and differentiation of normal urothelium. The contribution to UCB progression is still elusive. Differential expression of GRHL3 was assessed in normal human urothelium and in non-invasive and invasive bladder cancer cell lines. The contribution of GRHL3 to cell proliferation, viability and invasion in UCB cell lines was determined by gain- and loss-of-function assays in vitro and in an organ culture model using de-epithelialized porcine bladders. GRHL3 expression was detectable in normal human urothelial cells and showed significantly higher mRNA and protein levels in well-differentiated, non-invasive RT4 urothelial carcinoma cells compared to moderately differentiated RT112 cells. GRHL3 expression was absent in anaplastic and invasive T24 cells. Ectopic de novo expression of GRHL3 in T24 cells significantly impaired their migration and invasion properties in vitro and in organ culture. Its downregulation improved the invasive capacity of RT4 cells. The results indicate that GRHL3 may play a role in progression and metastasis in UCB. In addition, this work demonstrates that de-epithelialized porcine bladder organ culture can be a useful, standardized tool to assess the invasive capacity of cancer cells.


Asunto(s)
Carcinoma/genética , Proteínas de Unión al ADN/genética , Factores de Transcripción/genética , Neoplasias de la Vejiga Urinaria/genética , Urotelio/metabolismo , Animales , Carcinoma/patología , Carcinoma de Células Transicionales , Diferenciación Celular/genética , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia , Técnicas de Cultivo de Órganos , Porcinos , Neoplasias de la Vejiga Urinaria/patología , Urotelio/patología
17.
Int J Nanomedicine ; 16: 1361-1376, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33658777

RESUMEN

Object: High targeting and efficient cytotoxicity toward tumor cells endow NPs excellent anti-tumor activity. Herein, a peptide polymer possessing dual-targeting ability and double therapeutic activity was developed and named TGMF, which can form NPs through self-assembly. It is composed of four functional modules: 1) Active targeting peptide TMTP1 (T) deliver NPs to tumors specifically; 2) Therapeutic peptide GO-203 (G), which can significantly inhibit tumor growth by disrupting the redox balance in cells; 3) A passively targeted enzyme-responsive peptide PLGLGA (M), which can be cleaved specifically by metalloproteinase-2 (MMP-2) highly expressed in the tumor microenvironment (TME); and 4) Hexadecyl (F), which has strong hydrophobicity, can promote the self-assembly of TGMF NPs. Methods: Five modular peptide probes, namely, TGF, TMF, TGM, GMF, and TGMF were synthesized and self-assembled into NPs in solution. The characterization, enzyme reactivity, and cytotoxicity of NPs were evaluated in vitro, and the pharmacokinetics, bio-distribution, anti-tumor activity of NPs were investigated in vivo. In addition, transcriptome sequencing identified the intracellular signaling pathway-related genes involved in the anti-tumor effect of TGMF. Results: Upon enzyme cleavage, two types of nanostructure, NPs and nanofibers (NFs), were detected under TEM. Moreover, the cytotoxicity and anti-invasion activity of TGMF against tumor cells used were strongest among the five modular probes examined in vitro. TGMF increased reactive oxygen species (ROS) levels in cytoplasm and produced numerous NFs in extracellular interval and intracellular space. Transcriptome sequencing revealed that TGMF caused 446 genes' down-regulation and 270 genes' up-regulation in HeLa cells. In vivo, TGMF has a good anti-tumor effect, effectively prolonging the survival time of HeLa-tumor-bearing mice without systemic side effects. Conclusion: Integration of multiple functional modules into NPs could be a promising strategy for the future of nanomedicine design towards tumor treatment.


Asunto(s)
Antineoplásicos/uso terapéutico , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Femenino , Células HeLa , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Nanofibras/química , Nanofibras/ultraestructura , Nanopartículas/ultraestructura , Invasividad Neoplásica , Metástasis de la Neoplasia , Neoplasias/genética , Péptidos/química , Polímeros/química , Análisis de Componente Principal , Especies Reactivas de Oxígeno/metabolismo , Transcriptoma/efectos de los fármacos , Transcriptoma/genética , Microambiente Tumoral/efectos de los fármacos
18.
Biomed Environ Sci ; 34(2): 139-151, 2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33685573

RESUMEN

Objective: The underlying mechanism of Ezrin in ovarian cancer (OVCA) is far from being understood. Therefore, this study aimed to assess the role of Ezrin in OVCA cells (SKOV3 and CaOV3) and investigate the associated molecular mechanisms. Methods: We performed Western blotting, reverse transcription-quantitative polymerase chain reaction, MTT, cell colony, cell wound healing, transwell migration and invasion, RhoA and Rac active pull down assays, and confocal immunofluorescence experiments to evaluate the functions and molecular mechanisms of Ezrin overexpression or knockdown in the proliferation and metastasis of OVCA cells. Results: The ectopic expression of Ezrin significantly increased cell proliferation, invasiveness, and epithelial-mesenchymal transition (EMT) in OVCA cells. By contrast, the knockdown of endogenous Ezrin prevented OVCA cell proliferation, invasiveness, and EMT. Lastly, we observed that Ezrin can positively regulate the active forms of RhoA rather than Rac-1 in OVCA cells, thereby promoting robust stress fiber formation. Conclusion: Our results indicated that Ezrin regulates OVCA cell proliferation and invasiveness by modulating EMT and induces actin stress fiber formation by regulating Rho-GTPase activity, which provides novel insights into the treatment of the OVCA.


Asunto(s)
Proteínas del Citoesqueleto/metabolismo , Neoplasias Ováricas/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Proteínas del Citoesqueleto/genética , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Invasividad Neoplásica , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Fibras de Estrés/genética , Fibras de Estrés/metabolismo , Proteína de Unión al GTP rhoA/genética , Proteína de Unión al GTP rhoA/metabolismo
19.
Int J Nanomedicine ; 16: 1961-1976, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33727809

RESUMEN

Introduction: Metastatic breast cancer seriously harms women's health and is currently the tumour type with the highest mortality rate in women. Recently, the combinatorial therapeutic approaches that integrate anti-cancer drugs and genetic agents is an attractive and promising strategy for the treatment of metastatic breast cancer. Moreover, such a combination strategy requires better drug carriers that can effectively deliver the cargo to the breast cancer cells and achieve controlled release in the cells to achieve better therapeutic effects. Methods: The tumour-targeted and redox-responsive mesoporous silica nanoparticles (MSNs) functionalised with DNA aptamers (AS1411) as a co-delivery system was developed and investigated for the potential against metastatic breast cancer. Doxorubicin (Dox) was loaded onto the MSNs, while AS1411 and a small interfering RNA (siTIE2) were employed as gatekeepers via attachment to the MSNs with redox-sensitive disulfide bonds. Results: The controlled release of Dox and siTIE2 was associated with intracellular glutathione. AS1411 mediated the targeted delivery of Dox by increasing its cellular uptake in metastatic breast cancer, ultimately resulting in a lower IC50 in MDA-MB-231 cells (human breast cancer cell line with high metastatic potency), improved biodistribution in tumour-bearing mice, and enhanced in vivo anti-tumour effects. The in vitro cell migration/invasion assay and in vivo anti-metastatic study revealed synergism in the co-delivery system that suppresses cancer cell metastasis. Conclusion: The tumour-targeted and redox-responsive MSN prepared in this study are promising for the effective delivery and controlled release of Dox and siTIE2 for improved treatment of metastatic breast cancer.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/uso terapéutico , Nanopartículas/química , ARN Interferente Pequeño/administración & dosificación , Dióxido de Silicio/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada/farmacología , Preparaciones de Acción Retardada/uso terapéutico , Doxorrubicina/farmacología , Portadores de Fármacos/química , Endocitosis/efectos de los fármacos , Femenino , Células HEK293 , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/ultraestructura , Invasividad Neoplásica , Metástasis de la Neoplasia , Oxidación-Reducción , Porosidad , ARN Interferente Pequeño/farmacología , Distribución Tisular/efectos de los fármacos
20.
Anticancer Res ; 41(3): 1203-1212, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788711

RESUMEN

BACKGROUND/AIM: Hepatocellular carcinoma (HCC) remains one of the biggest medical issues. Pigment epithelial-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors. PEDF interacts with its two receptors, adipose triglyceride lipase (ATGL) and laminin receptor (LR). MATERIALS AND METHODS: We conducted immunohistochemical staining for PEDF, LR and ATGL in 151 resected HCCs and their background liver tissues. RESULTS: High expression of LR in HCC was associated with high histological grade and portal vein invasion, while high expression of PEDF in HCC was associated with absence of portal vein invasion. High LR expression in background liver was statistically associated with low serum albumin levels and was an independent prognostic factor of worse outcomes. No cases with more than 5% fatty degeneration in the background liver tissue showed high PEDF expression. CONCLUSION: PEDF/LR/ATGL could be potential biomarkers in HCC and various chronic hepatic disorders.


Asunto(s)
Carcinoma Hepatocelular/química , Proteínas del Ojo/análisis , Lipasa/análisis , Neoplasias Hepáticas/química , Hígado/química , Factores de Crecimiento Nervioso/análisis , Receptores de Laminina/análisis , Receptores de Neuropéptido/análisis , Serpinas/análisis , Carcinoma Hepatocelular/patología , Femenino , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/patología , Masculino , Invasividad Neoplásica , Pronóstico , Albúmina Sérica/análisis
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