RESUMEN

Immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) are associated with improved treatment efficacy in certain types of cancer. In the present study, we assessed the association between irAEs and ICI efficacy. Patients with esophageal squamous cell carcinoma (ESCC) who received ICI treatment were stratified into irAEs and non-irAE groups. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were used to evaluate the therapeutic efficacy of ICIs. Of the 78 ICI-treated ESCC patients, 39 developed irAEs. The median OS and PFS for all patients were 600 and 300 days, respectively. Median OS (P<0.001) and PFS (P<0.001) times of the patients with irAEs were longer than those in the non-irAE group. In addition, the DCR of the irAE group was higher than that of the non-irAE group (P=0.006). Univariate analysis indicated that the non-irAE group was associated with a relatively shorter OS [hazard ratio (HR)=3.687, 95% CI, 1.974-6.888, P<0.001] and PFS (HR=2.967, 95% CI, 1.691-5.204, P<0.001). The multifactorial analysis demonstrated that irAE status was an independent predictor of PFS (HR=3.564, 95% CI, 1.786-7.114, P<0.001) and OS (HR=3.288, 95% CI, 1.636-6.606, P=0.001). In conclusion, the present study demonstrated that irAEs could be used to predict improved treatment efficacy in patients with ESCC who received ICI therapy.

RESUMEN

BACKGROUND: Immune checkpoint inhibitors (ICIs) has shown remarkable benefit in the treatment of a range of cancer types, although it may initiate immune related adverse events (irAEs) in patients. Some studies have shown that there is a close relationship between the occurrence of irAEs and prognosis. In present study, we have attempted to establish whether the occurrence of irAEs after the use of anti PD-1 antibodies is associated with treatment efficacy in people with advanced gastric cancer (AGC). METHODS: This study included patients treated with the anti-PD-1 antibodies for AGC patients at The Fourth Hospital of Hebei Medical University. IrAEs were identified clinically and graded as per the National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.03. Efficacy was evaluated with objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS). The analysis was performed to determine the association between irAEs and clinical outcomes. RESULT: Of the 74 AGC patients in our study, 24 developed irAEs. The DCR of the irAE displayed a trend better than that of non-irAE group but without statistical difference (41.70% VS 6.0%, p = 0.118). Median PFS in the irAE group was superior to that in the non-irAE group (176 days VS 94 days, p = 0.001). Median OS also showed this trend of difference at borderline statistical level (292 days VS 239 days, p = 0.057). Multivariate analysis also demonstrated irAE (HR = 0.269, 95%CI: 0.088 to 0.822, p = 0.021) were associated independently with the better prognosis for AGC patients. CONCLUSION: In advanced gastric cancer treated with anti PD-1 antibodies, the occourence of irAEs might contribute to the improved prognosis.

Asunto(s)

Antineoplásicos Inmunológicos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Neoplasias Gástricas , Humanos , Nivolumab/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Neoplasias Gástricas/tratamiento farmacológico , Estudios Retrospectivos , Pronóstico

RESUMEN

Breast cancer (BRCA) is the most prevalent malignancy and the leading cause of death in women. Interleukin (IL) genes are critical in tumor initiation and control. Nevertheless, the prognosis value of the IL in BRCA remains unclear. We collected data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and 94 IL genes were identified from GeneCard. Based on the random forest (RF), least absolute shrinkage and selection operator (LASSO) analysis, and multivariate Cox regression analysis, we constructed an IL signature. GSE22219, GSE25065, and GSE21653 were derived as validation sets. The expression differences in the tumor microenvironment (TME), immunotherapy, and chemosensitivity of BRCA between the high- and low-risk groups were evaluated. Overall, 21 IL genes were selected to construct an IL risk model, of which IL18BP, IL17D, and IL23A were the first time identified as prognostic genes in BRCA. IL score could distinguish BRCA patients with inferior outcomes, and AUC of it was 0.70, 0.76, and 0.72 for 1-,3- and 5- years, respectively, which was also verified in GSE22219, GSE25065, and GSE21653 cohorts. Meanwhile, compared to luminal A and luminal B, HER2-positive and TNBC had significantly higher IL score. Besides, the high-risk group had a significantly higher prevalence of TP53 and TTN but a lower prevalence of PIK3CA, as well as higher tumor mutation burden (TMB) and neoantigen level. High- and low-risk groups exhibited notable differences in immunomodulators and tumor infiltrates immune cells (TIICs), and the high-risk group had significantly lower Tumor Immune Dysfunction and Exclusion (TIDE) score. Additionally, the high-risk group has more responders to immune or anti-HER2 combination therapy, whereas the low-risk group has higher sensitivity to docetaxel and paclitaxel. Consequently, we constructed a reliable risk model based on the IL genes, which can provide more information on both the risk stratification and personalizing management strategies for BRCA.

Asunto(s)

Neoplasias de la Mama , Microambiente Tumoral , Humanos , Femenino , Microambiente Tumoral/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Inmunoterapia , Factores Inmunológicos , Interleucinas

RESUMEN

ABSTRACT: Palbociclib has shown satisfactory outcomes when combined with endocrine therapy (ET) in hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC). However, data in Asia are currently scarce.This retrospective study aimed to evaluate the real-world effectiveness, sensitivity, and toxicity of palbociclib plus ET in HR+/HER2- MBC in North China. We recruited patients with HR+/HER2- MBC from August 2018 to July 2020 across 7 hospitals in North China. The primary endpoint was to evaluate progression-free survival (PFS) after initial progress on palbociclib therapy. The secondary endpoints included determining predictive biomarkers of palbociclib sensitivity and toxicity of palbociclib.A total of 54 patients were analyzed in this cohort with an estimated median follow-up time of 14.3 months. Patients who received palbociclib as a first-line treatment showed significantly prolonged PFS compared with those who received palbociclib as a second-line or beyond treatment (21.8 months vs 15.9 months vs 6.8 months) (P < .001). Besides, patients with Ki67 <30% (P = .024) and PR ≥20% (P = .041) in metastatic tumors had significantly longer PFS. The Cox proportional-hazards regression analyses proved that different lines (P = .001 in multivariate analysis), Ki67 <30% (P = .035 in multivariate analysis), and PR ≥20% (P = .045 in univariate analysis) in metastatic tumors affected PFS significantly. The most common adverse events were hematologic, with 31.48% of patients having neutropenia.Palbociclib plus ET significantly prolonged PFS for patients with HR+/HER2- MBC who received first-line therapy, with manageable toxicity. The values of Ki67 and PR in metastatic tumors may be potential predictive biomarkers of palbociclib sensitivity.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Piperazinas/uso terapéutico , Piridinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Inhibidores de la Aromatasa/administración & dosificación , Quinasa 4 Dependiente de la Ciclina , Femenino , Humanos , Antígeno Ki-67 , Metástasis de la Neoplasia , Piperazinas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Piridinas/efectos adversos , Receptores de Estrógenos/metabolismo , Estudios Retrospectivos , Resultado del Tratamiento

RESUMEN

BACKGROUND: Gastric cancer (GC) is a strong cause of global cancer mortality. Nucleotide excision repair (NER) can modulate platinum-based chemotherapeutic efficacy by removing drug-produced DNA damage. Some studies have found a link between excision repair cross complementation group 1 (ERCC1) rs2298881, one gene in NER pathway, and response to chemotherapy. However, the results have been disputed. METHODS: We conducted a meta-analysis to reevaluate the association between polymorphisms of NER gene (ERCC1 rs2298881) and the clinical outcomes in gastric cancer patients receiving platinum-based chemotherapy. Searching PubMed, Web of Science, EMBASE, Google Scholar, and China National Knowledge Infrastructure, 2 independent searchers found all pertinent literatures up to May 1, 2021. We enrolled studies according to consistent selection criteria, extracted and vitrified data. Crude odds ratios (ORs) and hazard ratios (HRs) with 95% confidence interval (CI) were applied to evaluate the effect of ERCC1 rs2298881 on patients treated by platinum-based chemotherapy. RESULTS: By the data gathered from 6 independent studies, 1940 cases diagnosed with gastric cancer and treated with chemotherapy were included, containing 1208 Good-Responders and 732 Poor-Responders. With a comprehensive meta-analysis, we found that the patients with ERCC1 rs2298881A allele had a worse response to chemotherapy than those who with rs2298881C allele under allelic model (A vs C), with the pooled OR of 0.780 (95% CI: 0.611-0.996, P = .046). And our analysis indicated that AA genotype was associated with unfavorable overall survival (HR = 1.540, 95% CI = 1.106-2.144, P = .011) compared with CC genotype. CONCLUSIONS: ERCC1 rs2298881 is suggested as a marker of clinical outcome in gastric cancer patients treated by platinum-based chemotherapy.

Asunto(s)

Antineoplásicos/uso terapéutico , Cisplatino/uso terapéutico , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Oxaliplatino/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Humanos , Polimorfismo de Nucleótido Simple , Pronóstico , Neoplasias Gástricas/mortalidad

RESUMEN

The mechanism of extracellular matrix induced tumor progression is poorly understood. Based on the TCGA database and clinical tumor tissues analysis, we observed abundant type I collagen expression in tumor tissues and poor overall survival in gastric patients with high integrin ß1 (ITGB1) expression. In vitro, our study found that 3D collagen culture promoted the capability of colony formation and growth in ITGB1 positive gastric cancer, whereas limited colony growth was observed in ITGB1 negative gastric cancer, suggesting the role of ITGB1 in type I collagen associated tumor progression. Mechanistically, we demonstrated that type I collagen was capable of promoting the activation of BCL9L/ß-catenin signaling pathway through ITGB1, thereby contributing to the gastric cancer development. Subsequently, ß-catenin signals further up-regulated the expression anti-apoptosis protein BCL2, leading to the chemo-resistance in gastric cancer cells. Blockade of ß-catenin signals efficiently improved the anticancer effects of chemotherapy, providing an innovative sight for clinical gastric cancer therapy.

Asunto(s)

Colágeno Tipo I/farmacología , Proteínas de Unión al ADN/metabolismo , Integrina beta1/metabolismo , Neoplasias Gástricas/metabolismo , Factores de Transcripción/metabolismo , beta Catenina/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Matriz Extracelular/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Integrina beta1/genética , Ratones , Ratones Endogámicos NOD , Ratones SCID , Transducción de Señal , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

PURPOSE: Vascular endothelial growth factor (VEGF) family members contribute greatly to the development and angiogenesis of hypervascular hepatocellular carcinoma (HCC). We have previously shown that Dicer inhibited HCC growth. In this study, we aimed to determine the relationship between Dicer and VEGF in HCC. METHODS: Gain-of-function studies were performed to determine the effect of different treatments on the proliferation, migration, and invasion of HCC cells. Expression of VEGF-A in xenograft tumor tissues was analysed using Western blotting, and that of CD31 using immunohistochemical analysis. RESULTS: We found that Dicer inhibited proliferation, migration and invasion of HCC cells by suppressing VEGF-A expression. Interestingly, VEGF-A165, which is the most prominent VEGF-A isoform, counteracted Dicer-induced inhibition of HCC cells. In addition, a monoclonal anti-VEGF antibody (bevacizumab) enhanced Dicer-induced inhibition of HCC in vitro and in vivo. Further, immunohistochemical analysis of CD31 indicated bevacizumab and Dicer synergized to reduce tumor microvessel density. CONCLUSION: Our data demonstrated that Dicer enhanced bevacizumab-related inhibition of HCC cell via the VEGF pathway; therefore, Dicer in coordination with bevacizumab may provide another potential approach for HCC therapy.

RESUMEN

The postoperative risk of stenosis is a complex issue, with risk factors including the status of human umbilical vein endothelial cells, the shear stress of dynamic blood flow, and blood physiology. Current research would benefit from in vitro models that can mimic the microenvironment of living vessels, to study the response of endothelial cells to stent placement. In this study, we constructed a digital pulse flow system based on a group of programmable solenoid valves, to mimic dynamic blood flows in the left coronary artery. Elastic artificial vessels, with internally cultured endothelial cells, were used to simulate vessel function and physiology. Based on this novel platform, we systematically explored cell proliferation and function in artificial vessels implanted with bare metal stents or drug-eluting stents, using unstented vessels as controls, under static and pulse flow conditions. The results indicate that the natural shear stresses of dynamic blood flow actually benefit endothelial cell attachment and proliferation. And drug-eluting stents showed stronger inhibition of cell proliferation than bare metal stents, but had a more negative effect on the synthesis of nitric oxide synthase (NOS), suggesting that drug elution might reduce the postoperative risk of restenosis, while increasing the risk of vasospasm. The results suggest that stent evaluation should include both the risk of restenosis and the effect on endothelial cells. Our simulation establishes a realistic in vitro model for pathological studies of restenosis and vasospasm, shows potential for evaluation of new stent designs, and could help develop individualised therapies for patients with atherosclerosis.

Asunto(s)

Aterosclerosis , Stents Liberadores de Fármacos , Constricción Patológica , Células Endoteliales , Humanos , Stents

RESUMEN

OBJECTIVE: To observe changes in the growth of fluorescence-labelled tumour cells in nude mice using small animal in vivo imaging technology and to compare the anti-tumour effects of the administration of bevacizumab monoclonal antibodies combined with chemotherapy at different time sequences. MATERIALS AND METHODS: Different time sequences of administration of bevacizumab monoclonal antibodies combined with the 5-fluorouracil and cisplatin (FP) chemotherapy regimen were used for intervention treatment of tumour growth in a subcutaneous xenograft model of human gastric cancer in nude mice. Tumour growth, that is, tumour volume, was evaluated with the changes in fluorescence signal strength and the inhibition rate. RESULTS: Compared with the control group (normal saline), experimental groups had a certain inhibition rate, while the tumour inhibition rate in the group with a bevacizumab treatment for 24 h followed by the FP chemotherapy regimen was the highest (68.42%). Moreover, the fluorescence signal strength changed significantly in all of the experimental groups. At the 3rd week of bevacizumab administration, the fluorescence signal value in the group with a bevacizumab treatment for 24 h followed by the FP chemotherapy regimen was the lowest, indicating this is the best treatment out of five groups. CONCLUSION: Bevacizumab monoclonal antibodies combined with chemotherapy had synergistic effects. The small animal in vivo imaging system could dynamically obtain long and short diameters of tumours and their fluorescence signal values; compared with traditional methods that calculate tumour inhibition rates by weighing tumours, this method was more sensitive and more objective for drug evaluation.

Asunto(s)

Antineoplásicos Inmunológicos/farmacología , Bevacizumab/farmacología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Animales , Antineoplásicos Inmunológicos/administración & dosificación , Bevacizumab/administración & dosificación , Biomarcadores , Cisplatino/administración & dosificación , Modelos Animales de Enfermedad , Quimioterapia Combinada , Fluorouracilo/administración & dosificación , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Desnudos , Terapia Molecular Dirigida , Neoplasias Gástricas/tratamiento farmacológico , Resultado del Tratamiento , Carga Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Gastric cancer is the fifth most common malignancy in the world, with Eastern Asia as one of areas with the highest incidence rates. Trastuzumab, a HER2-targeting antibody, combined with chemotherapy has been successfully employed for the gastric cancer patients with HER2 overexpression/amplification. However, trastuzumab resistance is a major problem in clinical practice. Here we observed that the trastuzumab-resistant gastric cancer cell line NCI-N87/TR expressed high levels of epithelial-mesenchymal transition factors and demonstrated increased migration and invasion capability compared with NCI-N87 cells. Downregulated E-cadherin and increased N-cadherin, TGF-ß, ZEB1, ZEB2, TWIST1, and Snail were detected in NCI-N87/TR cells. We also found that miR-200c was downregulated in NCI-N87/TR cells compared with parental cells NCI-87 by qRT-PCR. Treatment with TGF-ß downregulated the expression of miR-200c and upregulated ZEB2, and significantly decreased the trastuzumab sensitivity of NCI-N87 cells. miR-200c restored trastuzumab sensitivity and inhibited migration and invasion through suppressing ZEB1 and ZEB2. In summary, TGF-ß/ZEB2 axis plays an encouraging role in trastuzumab resistance of gastric cancer, while miR-200c overexpression downregulates ZEB1/ZEB2 and resensitizes drugs resistance. Our findings might provide a potential therapeutic strategy for trastuzumab resistance of gastric cancer.

Asunto(s)

Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , MicroARNs/biosíntesis , Proteínas de Neoplasias/metabolismo , ARN Neoplásico/biosíntesis , Neoplasias Gástricas , Factor de Crecimiento Transformador beta/metabolismo , Trastuzumab/farmacología , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Línea Celular Tumoral , Humanos , MicroARNs/genética , Proteínas de Neoplasias/genética , ARN Neoplásico/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Factor de Crecimiento Transformador beta/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética

RESUMEN

PURPOSE: To investigate the antitumor effects of the angiogenesis inhibitor bevacizumab combined with chemotherapy, and the application of in vivo imaging technology of growth of fluorescence-labelled gastric cancer (GC) in nude mice. METHODS: Twenty-five nude mice were randomly divided into 5 groups (A-E). Subcutaneous xenograft of human MGC803 cells was transplanted to nude mice, followed by different treatments for the groups, including A (bevacizumab combined with chemotherapy), B (24-h chemotherapy with FP followed by bevacizumab), C (bevacizumab 24-h followed by FP chemotherapy), D (bevacizumab only) and E (normal saline). Then, dynamic variation of tumor growth during 4 weeks was evaluated by calculating the tumor inhibition rate and fluorescence signal strength by in vivo imaging system. RESULTS: After 28-day treatment, fluorescence signal strength in the groups A-D changed significantly compared with the E (control) group, while tumor inhibition rate in C group was highest (68.42%). Furthermore, on the 4th week, the fluorescence signal value in C group was lowest. CONCLUSIONS: Administration of bevacizumab followed by chemotherapy was more effective therapeutic method for GC. The in vivo imaging could show off dynamic variation of tumors and was a sensitive and objective detection method.

Asunto(s)

Inhibidores de la Angiogénesis/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Bevacizumab/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Genes Reporteros , Humanos , Mediciones Luminiscentes , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Imagen Óptica/métodos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Factores de Tiempo , Transfección , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Elevated levels of vascular endothelial growth factor (VEGF) contribute to angiogenesis and serous cavity effusions. The present study evaluated the diagnostic and prognostic values of VEGF-A, -C and -D proteins in the serum, supernatant fluid and exfoliated cells of cancer patients with malignant effusions compared with patients with benign effusions. An enzyme-linked immunosorbent assay was used to detect levels of VEGF-A, -C and -D proteins in the sera of 79 cases (30 lung cancer, 21 gastric cancer and 28 benign effusions) and the supernatant fluid of 96 cases (38 lung cancer, 30 gastric cancer, and 28 benign effusion). Immunocytochemistry detected the expression of VEGF-A, -C and -D proteins in effusion cells from 71 cases (34 lung cancer, 17 gastric cancer and 20 benign effusions). The data were further investigated to determine whether there was an association between VEGF subtype expression and clinicopathological characteristics and prognosis. The expression levels of VEGF-A in the supernatant fluid were increased in the lung and gastric cancer patient samples compared with the benign effusions (P<0.05). The VEGF-A level in the supernatant fluid was significantly increased compared with the corresponding sera of patients with malignant effusion (P<0.05). VEGF-A, -C and -D proteins in the exfoliated cells from primary lung or gastric cancer effusions were expressed at 52.94, 70.58 and 82.35%, respectively, whereas their expression was not detected in the exfoliated cells from benign effusion, with the exception of mesothelial cells. The levels of VEGF-A and VEGF-C in the supernatant fluid levels and the cell levels of VEGF-A were inversely associated with age; in addition, VEGF-A levels in the supernatant fluid were associated with malignant and bloody effusion, and only cavity metastasis (P<0.05). Survival analysis demonstrated a relatively reduced survival time for patients with VEGF-A levels of >406.19 pg/ml in the supernatant fluid compared with patients with VEGF-A levels of ≤406.19 pg/ml (P=0.066). Serum VEGF-A, -C and -D levels exhibited no evident clinical significance in the diagnosis and prognosis of serous cavity effusions. VEGF-A in the supernatant fluid merits further study as a tumor marker in the clinical setting to discriminate benign from malignant effusions, while cellular VEGF-C and -D may contribute to the formation of malignant effusions.

RESUMEN

Although microRNA­33 (miR­33) family members are known to be involved in the regulation and balancing of cholesterol metabolism, fatty acid oxidation and insulin signaling, their functions in carcinogenesis are controversial and the underlying mechanisms have remained elusive. Gastric cancer is the fourth most common malignancy in the world; however, the dysregulation and function of miR­33 family members in gastric cancer have not been extensively studied. The present study reported that a miR­33 family member, miR­33a, was significantly downregulated in gastric cancer tissues and gastric cancer cell lines. Of note, the expression of miR­33a was inversely correlated with pathological differentiation and metastasis as well as gastric cancer biomarker CA199. A cell­counting kit­8 assay showed that transfection of the SGC­7901 gastric cell line with miR­33a­overexpression plasmid inhibited the capability of the cells to proliferate. Furthermore, overexpression of miR­33a led to cell cycle arrest of SGC­7901 cells in G1 phase. In addition, a luciferase reporter assay showed that miR­33a directly targeted cyclin­dependent kinase 6 (CDK6), cyclin D1 (CCND1) and serine/threonine kinase PIM­1. In gastric cancer specimens, the reduced expression of miR­33a was associated with increased expression of CDK­6, CCND1 and PIM1. However, only PIM1 expression was significantly increased in cancer tissues compared with that in their adjacent tissues. The present study revealed that miR­33a was downregulated in gastric cancer tissues and cell lines, while forced overexpression of miR­33a decreased CDK­6, CCND1 and PIM1 expression to inhibit gastric cancer cell proliferation by causing G1 phase arrest. miR­33a overexpression may therefore resemble an efficient strategy for gastric cancer therapy.

Asunto(s)

Adenocarcinoma/genética , Ciclina D1/genética , Quinasa 6 Dependiente de la Ciclina/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Proteínas Proto-Oncogénicas c-pim-1/genética , Neoplasias Gástricas/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Anciano , Antígenos de Carbohidratos Asociados a Tumores/genética , Antígenos de Carbohidratos Asociados a Tumores/metabolismo , Secuencia de Bases , Antígeno Carcinoembrionario/genética , Antígeno Carcinoembrionario/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Ciclina D1/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular/genética , Humanos , Masculino , MicroARNs/antagonistas & inhibidores , MicroARNs/metabolismo , Persona de Mediana Edad , Datos de Secuencia Molecular , Estadificación de Neoplasias , Oligonucleótidos/genética , Oligonucleótidos/metabolismo , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Transducción de Señal , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología

RESUMEN

Gastric cancer is one of the most common malignant tumors and one of the leading causes of cancer-related mortality. Recent studies have revealed that there is a difference in microRNA (miR/miRNA) profiles between cancerous and normal tissues. To find a potentially useful prognostic predictor and a promising therapeutic tool for gastric cancer, the present study investigated the expression and clinical significance of the miR-200 family in gastric cancer. The miR-200 family has five members: hsa-miR-200a, hsa-miR-200b, hsa-miR-200c, hsa-miR-141 and hsa-miR-429. In 46 clinical samples of gastric cancer and paired non-cancerous tissues, the present study observed that the expression levels of the miR-200 family in the cancer tissues were significantly lower than those in the non-cancerous tissues (P<0.001). Lower levels of the five family members were associated with histological grade and the presence of an intravascular cancer embolus (P<0.05). The results revealed that the miR-200 family is downregulated in gastric cancer, and that there are significant differences in the expression of the miR-200 family between normal and cancer tissues. The miR-200 family may therefore become a potentially useful prognostic predictor of the aggressiveness of gastric cancer and a possible therapeutic tool in affected patients.

RESUMEN

Gastric cancer is the fourth most common malignancy in the world. Although microRNA-200 (miR-200) family members are thought to play roles in tumorigenesis, their functions in carcinogenesis are tumor specific, and the underlying mechanism of action still remains elusive. Few studies to date have addressed the dysregulation and function of miR-200 family members in gastric cancer progression. Here, we report that the miR-200 family members, miR-200c and miR-141, were significantly downregulated in gastric cancer specimens and gastric cancer cell lines. Importantly, on clinical samples, the expression of miR-200c and miR-141 was inversely correlated with TNM stage, tumor invasion depth (T), tumor embolus and disease-free survival. Wound-healing assay results showed that co-transfected miR-200c/141 could inhibit the migration and invasion capability of the gastric cell line SGC-7901. We also found that miR-200c and miR-141 directly targeted zinc finger E-box-binding homeobox 1/2 (ZEB1/2) and upregulated E-cadherin expression. In specimens from gastric cancer patients, reduced expression of miR-200c/141 was associated with increased expression of ZEB1 and/or ZEB2. In addition, the downregulation of miR-200c and miR-141 was found to be due to a highly methylated CpG island located upstream of their genomic sequence and/or upregulated TGF-ß signaling. Treatment with the chemotherapeutic agent decitabine, a known DNA methyltransferase inhibitor, increased miR-200c/141 expression and ameliorated decreased expression of miR-200c/141 induced by TGF-ß in SGC-7901 cells. Our study revealed that miR-200c/141 was downregulated by CpG island methylation and TGF-ß signaling, which decreased ZEB1/2 expression and increased E-cadherin expression to inhibit migration and invasion of gastric cancer cells and provides powerful evidence for the application of decitabine in gastric cancer treatment.

Asunto(s)

Regulación Neoplásica de la Expresión Génica/genética , Proteínas de Homeodominio/biosíntesis , MicroARNs/biosíntesis , Proteínas Represoras/biosíntesis , Neoplasias Gástricas/patología , Factores de Transcripción/biosíntesis , Anciano , Western Blotting , Movimiento Celular/genética , Islas de CpG/genética , Metilación de ADN/genética , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Regulación hacia Abajo , Femenino , Proteínas de Homeodominio/genética , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Invasividad Neoplásica/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Represoras/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidad , Factores de Transcripción/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc , Homeobox 1 de Unión a la E-Box con Dedos de Zinc

RESUMEN

The present study was conducted in order to investigate the inhibitory effects of ginsenoside Rg3 combined with chemotherapy on Eca-109 esophageal squamous cell carcinoma (ESCC) in mice. Tumor xenograft models were established in the right forelimb of 20 BALB/c nude mice by subcutaneous injection. The tumor-bearing mice were randomly assigned to 4 treatment groups (n=5 per group) as follows: the control group (saline), the ginsenoside Rg3 alone group (6 mg/kg/day, once a day for 3 weeks), the chemotherapy alone group (paclitaxel 10 mg/kg/day + cisplatin 5 mg/kg/day on days 1, 7, 14 and 21) and the chemotherapy + Rg3 group (combined treatment). The length and width of the tumor were directly measured with calipers at different time points and the tumor volume (cm3) was calculated using the formula 0.52 × length × width2 every other day. The mice were sacrificed by cervical dislocation following completion of therapy, the tumors were removed and weighed and the expression levels of Ki-67 were determined by immunohistochemistry. The results indicated that the coadministration of ginsenoside Rg3 significantly enhanced the inhibitory effects of chemotherapy on tumor growth. In addition, the expression levels of Ki-67 in the chemotherapy + Rg3 group were significantly lower compared to those in the other 3 groups. The chemotherapy + Rg3 group also exhibited the lowest microvascular density among all four groups. These findings suggested that ginsenoside Rg3 may improve the antitumor efficacy of chemotherapy in Eca-109 ESCC in mice.

RESUMEN

Gastric cancer remains a worldwide burden as the second leading cause of cancer-related death. Drug resistance of chemotherapy looms as a major clinical obstacle to successful treatment. Recent evidence indicated that miRNA-200c can restore the sensitivity of NSCLC cells to cisplatin and cetuximab. The expression of miRNA-200c and RhoE were investigated in gastric cancer tissues and cells (SGC7901 and SGC7901/DDP) by qRT-PCR. A luciferase reporter assay was done to understand the potential correlation between miRNA-200c and RhoE. Pre-miR-200c was transfected in SGC7901/DDP cells to confirm whether miRNA-200c could regulate RhoE expression. RhoE was knocked down to explore the role of RhoE on sensitivity of chemotherapy in gastric cancer by MTT. Western blot analysis was performed to further explore the mechanism of RhoE in regulating drug resistance. The results showed that miRNA-200c was significantly lower in cancerous tissues than those in the paired normal tissues, whereas the expression of RhoE was just the opposite. The significant difference of miRNA-200c and RhoE were observed between SGC7901 cells and SGC7901/DDP cells. miRNA-200c has target sites in the 3'-UTR of RhoE mRNA by luciferase reporter assay. Transfection of pre-miR-200c reduces RhoE expression. Meanwhile, the knockdown of RhoE enhanced the sensitivity of SGC7901/DDP cells and changed expression of some genes. These suggested that miRNA-200c regulated the sensitivity of chemotherapy to cisplatin (DDP) in gastric cancer by possibly targeting RhoE.

Asunto(s)

MicroARNs/genética , Neoplasias Gástricas/genética , Proteínas de Unión al GTP rho/genética , Regiones no Traducidas 3' , Antineoplásicos/farmacología , Línea Celular Tumoral , Resistencia a Antineoplásicos , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Transfección

RESUMEN

The purpose of this study was to investigate the efficacy of Endostar combined with chemotherapy on human esophageal squamous cell carcinoma Eca-109 in mice. The tumor xenograft models were established and randomly assigned to 4 groups: control group, Endostar group (1.5 mg/kg day, once daily for 3 weeks), chemotherapy group (Paclitaxel 10 mg/kg day, Cisplatin 5 mg/kg day, for 1, 7, 14, 21 days), and chemotherapy + Endostar group (combination). The length and width of tumor were measured and the tumor volumes (cm(3)) were calculated every other day. Three weeks later, the mice were executed, and the tumor tissues were collected to weigh and analyse the histopathology and proliferation for tumor xenograft. The results demonstrated that the tumor volumes and weight in chemotherapy + Endostar group were significantly lower than that in other three groups. Meanwhile, the cell proliferation of tumor xenograft in combined treatment group was significantly lower than that in other three groups. It was concluded that Endostar combined with chemotherapy could obviously enhance the inhibitory effect on esophageal squamous cell carcinoma Eca-109 in mice.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Endostatinas/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Endostatinas/administración & dosificación , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago , Femenino , Humanos , Antígeno Ki-67/metabolismo , Ratones , Ratones Desnudos , Proteínas Recombinantes , Factores de Tiempo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína X Asociada a bcl-2/metabolismo