RESUMEN
Approximately 10% of gastric cancers are associated with Epstein-Barr virus (EBV). Tremella fuciformis polysaccharides (TFPs) are characterized by antioxidative and anti-inflammatory effects in different diseases. However, whether TFP improves EBV-associated gastric cancer (EBVaGC) has never been explored. The effects of TFP on EBV-infected GC cell viability were determined using a CCK-8 assay and flow cytometry. Western blotting and RT-qPCR were performed to explore the expression of ferroptosis-related proteins. The CCK-8 assay showed that TFP decreased EBV-infected GC cell viability in a dose- and time-dependent manner. Flow cytometry assays indicated that TFP significantly induced EBV-infected GC cell death. TFP also reduced the migratory capacity of EBV-infected GC cells. Furthermore, treatment with TFP significantly increased the mRNA levels of PTGS2 and Chac1 in EBV-infected GC cells. Western blot assays indicated that TFP suppressed the expression of NRF2, HO-1, GPX4 and xCT in EBV-infected GC cells. More importantly, overexpression of NRF2 could obviously rescue TFP-induced downregulation of GPX4 and xCT in EBV-infected GC cells. In summary, we showed novel data that TFP induced ferroptosis in EBV-infected GC cells by inhibiting NRF2/HO-1 signaling. The current findings may shed light on the potential clinical application of TFP in the treatment of EBVaGC.
Asunto(s)
Basidiomycota , Infecciones por Virus de Epstein-Barr , Ferroptosis , Neoplasias Gástricas , Humanos , Herpesvirus Humano 4/genética , Neoplasias Gástricas/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Sincalida/metabolismoRESUMEN
[This retracts the article DOI: 10.3892/ol.2021.12544.].
RESUMEN
Duodenal stump fistula is a rare but dangerous complication of gastric cancer surgery. Reinforcement of the duodenal stump was suggested as a useful method to prevent the occurrence of duodenal stump fistula. Although laparoscopic surgery has been established as a safe procedure for gastric cancer, it is acknowledged that the application of duodenal stump reinforcement is a demanding process in laparoscopic radical gastrectomy. This review aims to provide a concise description of the proposed reinforcement methods of duodenal stump after laparoscopic radical gastrectomy for gastric cancer by summarizing the relevant literature written in English. The thorough knowledge of these reinforcement techniques may help surgeons to find the most suitable reinforcement method of duodenal stump for patients.
RESUMEN
Introduction: Colorectal cancer is one of the most prevalent life-threatening malignant tumors with high incidence and mortality. However, the efficacy of current therapeutic regimens is very limited. Regorafenib has been approved for second- or third-line treatment of patients who are refractory to standard chemotherapy diagnosed with metastatic colorectal cancer, but its clinical efficacy needs to be further improved. Accumulating evidence demonstrates that statins also possess potent anticancer activities. However, whether regorafenib and statins pose synergistic anticancer effects in colorectal cancer is still unclear. Methods: Sulforhodamine B (SRB) assays were applied to evaluate the anti-proliferative activity of regorafenib or/and rosuvastatin in vitro, and immunoblotting analysis were applied to detect the effects of regorafenib/rosuvastatin combined treatment on mitogen-activated protein kinase (MAPK) signaling and apoptosis-related proteins. MC38 tumors were applied to investigate the synergistic anticancer effects of regorafenib in combination with rosuvastatin in vivo. Results: We found that regorafenib in combination with rosuvastatin exerted significant synergistic inhibition against colorectal cancer growth in vitro and in vivo. Mechanistically, regorafenib and rosuvastatin combination synergistically suppressed MAPK signaling, a crucial signaling pathway promoting cell survival, as indicated by the reduction of phosphorylated MEK/ERK. In addition, regorafenib in combination with rosuvastatin synergistically induced the apoptosis of colorectal cancer in vitro and in vivo. Discussion: Our study demonstrated the synergistic anti-proliferative and pro-apoptotic effects of regorafenib/rosuvastatin combined treatment in colorectal cancer in vitro/vivo and might potentially be evaluated as a novel combination regimen for clinical treatment of colorectal cancer.
RESUMEN
Larotrectinib (Lar) is a highly selective and potent small-molecule inhibitor used in patients with tropomyosin receptor kinase (TRK) fusion-positive cancers, including colon cancer. However, the underlying molecular mechanisms specifically in patients with colon cancer have not yet been explored. Our data showed that Lar significantly suppressed proliferation and migration of colon cancer cells. In addition, Lar suppressed the epithelial-mesenchymal transition (EMT) process, as evidenced by elevation in E-cadherin (E-cad), and downregulation of vimentin and matrix metalloproteinase (MMP) 2/9 expression. Furthermore, Lar was found to activate autophagic flux, in which Lar increased the ratio between LC3II/LC3I and decreased the expression of p62 in colon cancer cells. More importantly, Lar also increased AMPK phosphorylation and suppressed mTOR phosphorylation in colon cancer cells. However, when we silenced AMPK in colon cancer cells, Lar-induced accumulation of autolysomes as well as Lar-induced suppression of the EMT process were significantly diminished. An in vivo assay also confirmed that tumour volume and weight decreased in Lar-treated mice than in control mice. Taken together, this study suggests that Lar significantly suppresses colon cancer proliferation and migration by activating AMPK/mTOR-mediated autophagic cell death.
Asunto(s)
Muerte Celular Autofágica , Neoplasias del Colon , Ratones , Animales , Proteínas Quinasas Activadas por AMP/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Autofagia , Neoplasias del Colon/tratamiento farmacológico , Transición Epitelial-Mesenquimal , Línea Celular Tumoral , Proliferación Celular/fisiologíaRESUMEN
Interleukin-15 (IL-15) is a promising candidate for cancer immunotherapy due to its potent immune-activating effects. There are several IL-15 molecules currently in clinical trials but facing shortages of poor half-life, circulation instability, or complicated production and quality control processes. The aim of this study is to design a novel IL-15 superagonist to set out the above difficulties, and we constructed F4RLI consisting of the GS-linker spaced IgG4 Fc fragment, soluble IL-15 Rα (sIL-15Rα), and IL-15(N72D). Using a single plasmid transient transfection in HEK293E cells, the matured F4RLI was secreted in the form of homodimer and got purified by an easy step of protein A affinity chromatography. The F4RLI product can significantly stimulate the proliferation of human CD3+CD8+ T cells and NK cells in vitro. Meanwhile, F4RLI greatly extended the half-life and prolonged the exposure of IL-15 in mice nearly by 28- and 200-fold, respectively, in comparison with that of the IL-15 monomer. In vivo, F4RLI vastly expanded mouse splenic CD8+ T lymphocytes, illustrating its potential in tumor immunotherapy. Further studies showed that the combination of F4RLI with the immune checkpoint blocker atezolizumab played a synergistic effect in treating MC38 mouse tumor by increasing the percentage of CD8+ T cells in tumor tissue. Moreover, the combination therapy of F4RLI with the angiogenesis inhibitor bevacizumab resulted in significant tumor growth suppression in a xenograft human HT-29 mouse model. Overall, our results demonstrate a homodimeric IL-15 superagonist F4RLI with advances in manufacturing processes and biopharmaceutical applications for cancer immunotherapy. KEY POINTS: ⢠The homodimeric structure of F4RLI facilitates its easy production processes and quality control. ⢠The fusion with Fc and sIL-15Rα extends the plasma half-life of IL-15 by about 28-fold. ⢠F4RLI can play synergistic antitumor activity with the PD-1/PD-L1 checkpoint inhibitor or angiogenesis inhibitor.
Asunto(s)
Productos Biológicos , Interleucina-15 , Receptor de Muerte Celular Programada 1 , Animales , Humanos , Ratones , Inhibidores de la Angiogénesis/farmacología , Antígeno B7-H1/metabolismo , Bevacizumab/farmacología , Productos Biológicos/farmacología , Linfocitos T CD8-positivos , Línea Celular Tumoral , Semivida , Inhibidores de Puntos de Control Inmunológico/farmacología , Fragmentos Fc de Inmunoglobulinas/genética , Inmunoglobulina G/metabolismo , Inmunoterapia/métodos , Interleucina-15/agonistas , Receptor de Muerte Celular Programada 1/metabolismo , Antineoplásicos/farmacologíaRESUMEN
Nowadays, pancreatic cancer has been recognized as one of the most fatal malignancies worldwide, the molecular mechanism of which is still not fully understood. In this study, we aimed to uncover the fundamental functions of the eukaryotic translation initiation factor 3H subunit (EIF3H) in the development and progression of pancreatic cancer. Firstly, the results of immunohistochemical (IHC) staining revealed that EIF3H was highly expressed in pancreatic cancer. Moreover, lentiviruses were used to deliver shRNAs into pancreatic cancer cells for silencing EIF3H. Furthermore, the loss-of-function assays demonstrated that knockdown of EIF3H could inhibit the progression of pancreatic cancer cells by reducing proliferation capacity, promoting apoptosis, arresting cell cycle in G2 and suppressing cell migration. In summary, EIF3H may play a critical role in the development and progression of pancreatic cancer, which possesses the potential to act as a therapeutic target for pancreatic cancer treatment.
Asunto(s)
Factor 3 de Iniciación Eucariótica , Neoplasias Pancreáticas , Apoptosis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Factor 3 de Iniciación Eucariótica/genética , Factor 3 de Iniciación Eucariótica/metabolismo , Humanos , Neoplasias Pancreáticas/genética , Neoplasias PancreáticasRESUMEN
Gastric cancer is one of the first malignant cancers in the world and a large number of people die every year due to this disease. Many genetic and epigenetic risk factors have been identified that play a major role in gastric cancer. HOTAIR is an effective epigenetic agent known as long noncoding RNA (lncRNA). HOTAIR has been described to have biological functions in biochemical and cellular processes through interactions with many factors, leading to genomic stability, proliferation, survival, invasion, migration, metastasis, and drug resistance. In the present article, we reviewed the prognostic value of the molecular mechanisms underlying the HOTAIR regulation and its function in the development of Gastric Cancer, whereas elucidation of HOTAIR-protein and HOTAIR-DNA interactions can be helpful in the identification of cancer processes, leading to the development of potential therapeutic strategies.
RESUMEN
Background: We aimed to evaluate the effects of lncRNA PTV1 on colon cancer proliferation and migration via the Wnt6/ß-catenin2 pathway. Materials and Methods: A total of 117 colon cancer and normal adjacent tissue samples were collected. LncRNA PVT1 and miR-1207-5p expressions in these samples and colon cancer cell lines were detected by Quantitative reverse transcription-polymerase chain reaction (qRT-PCR). LncRNA PVT1-silencing cells and miR-1207-5p-overexpressing Caco-2-siPVT1 cells were constructed, respectively. The effects of lncRNA PVT1 silencing on cell proliferation were assessed by MTT and colony formation assays. The effects on invasion and migration were tested by Transwell and scratch assays respectively. The targeting regulatory relationship between miR-1207-5p and Wnt6 was analyzed by a dual-luciferase reporter assay. The relationship between lncRNA PVT1 and miR-1207-5p was studied by RNA-binding protein immunoprecipitation and RNA pull-down assays. The expressions of proteins in the Wnt6/ß-catenin2 pathway were detected by Western blotting. Results: The lncRNA PVT1 mRNA expression in colon cancer tissue was significantly higher than that in normal adjacent tissue (p < 0.05). The expression in lncRNA PVT1-silencing cells was significantly down-regulated (p < 0.05). The colonies of Caco-2-siPVT1 cells decreased, accompanied by a reduced number of cells penetrating Matrigel and migration (p < 0.05). Compared with siPVT1 + NC group, the number of colonies and migration of siPVT1 + miR-1207-5p-overexpressing group increased significantly (p < 0.05). There was a targeting relationship between miR-1207-5p and PVT1. MiR-1207-5p had a targeted binding site with Wnt6. The protein expressions of Wnt6/ß-catenin2 in Caco-2-siPVT1 group were significantly lower than those of control and Caco-2-siNC groups (p < 0.05). Conclusion: LncRNA PVT1 was highly expressed in colon cancer. It may enhance the proliferation and migration of colon cancer cells by up-regulating miR-1207-5p level and enhancing the Wnt6/ß-catenin2 pathway.
Asunto(s)
Neoplasias del Colon , MicroARNs , ARN Largo no Codificante , Vía de Señalización Wnt , beta Catenina , Células CACO-2 , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Invasividad Neoplásica , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
It has been demonstrated in many studies that the polymorphism of Ras association domain family 1 isoform A (RASSF1A) is related to tumor risk; however, this conclusion remains a controversy. In this study, we systemically retrieved relevant studies in electronic databases such as PUBMED, and EMBASE, and calculated odds ratios (ORs) as well as relevant 95% confidence intervals (CIs). Besides, meta-package in STATA version 12.0 was used. This meta-analysis finally included altogether 12 studies with 16 case-control articles. According to our data, the polymorphism of RASSF1A Ala133Ser was associated with tumor risk (Ser vs. Ala: OR = 1.68,95% CI = 1.20-2.36; Ala/Ser vs. Ala/Ala:OR = 1.63,95% CI = 1.16-2.27; Ser/Ser vs. Ala/Ala:OR = 3.06,95% CI = 1.91-4.89; Recessive model:OR = 2.67, 95% CI = 1.66-4.32; Dominant model: OR =1.72, 95% CI =1.20-2.45). Further, subgroup analyses stratified based on race and cancer type indicated this polymorphism is related to lung cancer(LC) and hepatocellular carcinoma(HCC) susceptibility in Asians.In conclusion, we found that RASSF1A Ala133Ser polymorphism increased LC and HCC risk in Asians, which requires large-scale, delicately-designed researches for verification.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Humanos , Oportunidad Relativa , Polimorfismo Genético , Polimorfismo de Nucleótido SimpleRESUMEN
Acute pancreatitis (AP) is an inflammatory disorder that has been associated with systemic inflammatory response syndrome. Ginsenoside Rg3 is a major active component of Panax ginseng, which has been demonstrated to exert potent protective effects on hyperglycemia and diabetes. However, it remains to be determined whether Rg3 ameliorates AP. Thus, an in vitro AP cell model was established in the present study by exposing AR42J cells to cerulein (Cn). AR42J cell viability was increased in the Rg3treated group as compared with the Cnexposed group. Simultaneously, the number of dead AR42J cells was decreased in the Rg3treated group compared with the group treated with Cn only. Furthermore, following treatment with Rg3, the production of malondialdehyde (MDA) and ferrous ion (Fe2+) in the AR42J cells was reduced, accompanied by increased glutathione (GSH) levels. Western blot analysis revealed that the decrease in glutathione peroxidase 4 (GPX4) and cystine/glutamate transporter (xCT) levels induced by Cn were reversed by Rg3 treatment in the AR42J cells. Mice treated with Cn exhibited increased serum amylase levels, as well as increased levels of TNFα, IL6, IL1ß, pancreatic MDA, reactive oxygen species (ROS) and Fe2+ production. Following Rg3 treatment, ROS accumulation and cell death were decreased in the pancreatic tissues compared with the AP group. Furthermore, in the pancreatic tissues of the AP model, the expression of nuclear factorerythroid factor 2related factor 2 (NRF2)/heme oxygenase 1 (HO1)/xCT/GPX4 was suppressed. In comparison, the NRF2/HO1/xCT/GPX4 pathway was activated in pancreatic tissues following Rg3 administration. Taken together, the present study, to the best of our knowledge, is the first to reveal a protective role for Rg3 in mice with AP by suppressing oxidative stressrelated ferroptosis and the activation of the NRF2/HO1 pathway.
Asunto(s)
Ferroptosis , Pancreatitis , Enfermedad Aguda , Animales , Ceruletida , Ginsenósidos , Glutatión , Hemo-Oxigenasa 1/metabolismo , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Pancreatitis/tratamiento farmacológico , Especies Reactivas de OxígenoRESUMEN
In this study, we examined whether and how miR-545 modulates ferroptosis in colorectal cancer (CRC). HT-29 and HCT-116 human CRC cell viability was examined using a CCK-8 assay and malondialdehyde (MDA) and Fe2+ levels were measured after treatment with the ferroptosis inducers Eradicator of Ras and ST (erastin) and Ras selective lethal 3 (RSL3) with or without miR-545 overexpression or knockdown vectors. Our results demonstrate that miR-545 overexpression inhibited, while miR-545 knockdown further increased, erastin and RSL3-induced upregulation of MDA, reactive oxygen species (ROS), and Fe2+ levels. Similarly, miR-545 overexpression partially reversed, while miR-545 knockdown enhanced, the erastin and RSL3-induced reduction in HT-29 and HCT-116 cell survival rates. Transferrin (TF) was identified as a target gene of miR-545. To determine whether miR-545 suppresses ferroptosis via TF, we overexpressed TF in HT-29 and HCT-116 cells. We found that TF overexpression blocked miR-545-induced changes in ROS, MDA, and Fe2+ levels in HT-29 and HCT-116 cells, thereby inducing CRC cell death. An in vivo assay showed that inhibition of miR-545 decreased tumor growth in nude mice treated with erastin. Together, these findings indicate that miR-545 promotes CRC cell survival by suppressing TF.
Asunto(s)
Supervivencia Celular , Neoplasias Colorrectales/metabolismo , Ferroptosis , MicroARNs/genética , Transducción de Señal , Animales , Neoplasias Colorrectales/genética , Células HCT116 , Humanos , Ratones , Ratones Desnudos , Piperazinas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Undifferentiated embryonal sarcoma of the liver (UESL) is a rare liver tumour that occurs mainly in children. Herein, we aimed to identify any differences in clinical characteristics and survival between adult and paediatric patients with UESL. METHODS: From 1975 to 2015 in the Surveillance, Epidemiology and End Results (SEER) database, patients diagnosed with UESL were identified and divided into paediatric (<18 years) and adult (≥18 years) groups. We then compared the clinical characteristics, management, and overall survival (OS) of adults and children diagnosed with UESL. RESULTS: We analysed 113 patients with UESL (81 children and 32 adults). UESL was significantly more common in adult male than paediatric male patients (71.9% vs. 48.2%; P = 0.022). When compared to adult patients, paediatric patients were more likely to receive chemotherapy (93.8% vs. 65.6%; P < 0.001). Adults had a significantly worse OS than paediatric patients (5-year OS, 30.0% vs. 81.2%; P < 0.001). Univariate analysis found that adult age, surgical therapy and chemotherapy were associated with OS. Multivariate analysis revealed that adult age, SEER summary stage and surgical therapy were independent prognostic factors for OS. CONCLUSIONS: UESL had a male predominance among adult patients. Moreover, the prognosis of adult patients with UESL was significantly worse than that of paediatric patients. Surgery and chemotherapy should be considered in the treatment of patients with UESL.
Asunto(s)
Neoplasias Hepáticas , Sarcoma , Neoplasias de los Tejidos Blandos , Niño , Humanos , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/terapia , Masculino , Análisis Multivariante , Sarcoma/epidemiología , Sarcoma/terapiaRESUMEN
BACKGROUND: Colorectal cancer (CRC) represents one of the major malignant cancers in the world. It has been demonstrated that long non-coding RNAs (lncRNAs) can cause great influences on various human cancers. Though MCF.2 cell line derived transforming sequence like antisense RNA 1 (MCF2L-AS1) and its carcinogenic effect in CRC has been elucidated by several previous researches, the underlying mechanism remains unknown. AIM: We aimed at exploring the function and regulatory mechanism of MCF2L-AS1 in CRC. METHODS: MCF2L-AS1 expression in CRC cells was tested via RT-qPCR assay. The effects of MCF2L-AS1 on the biological properties of CRC cells were testified through functional experiments. The molecular mechanism of MCF2L-AS1 was verified through mechanism experiments. RESULTS: MCF2L-AS1 was highly expressed in CRC cells, and it could enhance the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process of CRC cells. MiR-105-5p was sponged by MCF2L-AS1 in CRC cells and Ras-related protein Rab-22A (RAB22A) was verified to be the downstream target of miR-105-5p. It was verified through rescue assays that RAB22A overexpression or miR-105-5p silencing could reverse the repressive impact of MCF2L-AS1 silencing on CRC progression. CONCLUSION: MCF2L-AS1 accelerated the malignant development of CRC cells by targeting the miR-105-5p/RAB22A axis.
Asunto(s)
Neoplasias Colorrectales/metabolismo , MicroARNs/metabolismo , Proteínas de Neoplasias/metabolismo , Factores de Intercambio de Guanina Nucleótido Rho/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Apoptosis , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Silenciador del Gen , Humanos , MicroARNs/genética , Invasividad NeoplásicaRESUMEN
BACKGROUND: We performed a meta-analysis to investigate the efficacy of complete omentectomy (CO) in patients undergoing radical gastrectomy for gastric cancer. METHODS: We conducted a literature search in PubMed, Web of Science, and the Cochrane Library databases for clinical research that compared CO with non-complete omentectomy (NCO). These articles were published prior to April 2021. Overall survival (OS) rates, relapse-free survival (RFS) rates, recurrence rates, operation times, estimates of blood loss, numbers of harvested lymph nodes, complications, and lengths of hospital stays were compared using relative risks (RRs) and weighted mean differences (WMDs). RevMan 5.3 software was used for statistical analysis. RESULTS: Nine studies that included 3329 patients (1960 in the CO group) and 1369 in the NCO group comprised the analysis. The meta-analysis showed that CO was associated with a decreased 3-year OS rate (RR = 0.94, 95% CI 0.90-0.98, P = 0.005) and 5-year OS rate (RR = 0.93, 95% CI 0.88-0.98, P = 0.007). However, it was not associated with the 3-year RFS rate (RR = 0.97, 95% CI 0.90-1.04, P = 0.44), 5-year RFS (RR = 0.98, 95% CI 0.90-1.06, P = 0.60), or recurrence rate (RR = 1.17, 95% CI 0.95-1.45, P = 0.15) compared to the NCO group. For surgical-related outcomes, significant heterogeneity existed between the studies. Compared to the NCO group, CO was found to be associated with significantly more estimated blood loss (WMD = 250.90, 95% CI 105.90-396.28, P = 0.0007) and less harvested lymph nodes (WMD = - 3.59, 95% CI - 6.88, - 0.29, P = 0.03). Although, there was no significant difference in the surgical time (WMD = 15.93, 95% CI - 0.21, 32.07, P = 0.05). No statistically significant differences were observed in the rates of overall (P = 0.79) and major complications (P = 0.90), or the lengths of hospital stays (P = 0.11) between the two groups. CONCLUSIONS: Based on the available evidence, CO is not superior to NCO in terms of survival. CO is not recommended as a routine surgery for gastric cancer. Future well-designed high-quality RCTs are warranted.
Asunto(s)
Laparoscopía , Neoplasias Gástricas , Gastrectomía/efectos adversos , Humanos , Recurrencia Local de Neoplasia , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Neoplasias Gástricas/cirugía , Resultado del TratamientoRESUMEN
The aim of the present study was to determine the expression and diagnostic value of exosomal miR-130a-3p in the serum of patients with differentiated thyroid cancer (DTC). Exosomes were isolated from the serum of patients with DTC and were identified using transmission electron microscopy. A novel exosomal miRNA, miR-130a-3p, was found to be significantly decreased in the serum of patients with DTC compared with those with benign thyroid tumors and healthy controls. Further study revealed that exosomal miR-130a-3p was correlated with the malignant characteristics of DTC, including tumor diameter, lymph node metastasis (LNM) and higher TNM stage. Receiver operating characteristic curve analysis demonstrated that the area under the curve of exosomal miR-130a-3p was better compared with that of TgAb and Tg in patients with DTC. More importantly, the combined use of exosomal miR-130a-3p, TgAb and Tg significantly enhanced the sensitivity and specificity, indicating that exosomal miR-130a-3p is a sensitive biomarker for DTC. A dual luciferase reporter assay indicated that insulin-like growth factor (IGF)-1 was a target gene of miR-130a-3p. Pearson's correlation analysis revealed a negative correlation between serum IGF-1 and serum exosomal miR-130a-3p levels. More importantly, exosomes from patients with DTC increased the expression of IGF-1 and p-PI3K/p-AKT, but these effects were abolished by siRNA targeting IGF-1 in TPC-1 cells. Taken together, the findings of the present study indicated that reduced exosomal miR-130a-3p levels were associated with the risk of DTC and may be used as a biomarker for the diagnosis of DTC.
RESUMEN
BACKGROUND: This study aimed to analyze the relative expression of Eukaryotic Translation Initiation Factor 3 Subunit B (EIF3B) in pancreatic cancer and elucidate its contribution to this disease. METHODS: Relative expression of EIF3B in pancreatic cancer was analyzed by immunohistochemistry. Cell viability was determined by the MTT assay and cell proliferation was measured by direct cell counting. Cell apoptosis was detected by Annexin V staining followed by flow cytometry analysis, and cell cycle was analyzed by PI staining. The differential expression gene analysis was performed by microarray. Tumor progression in response to EIF3B deficiency in vivo was investigated using the xenograft tumor model. RESULTS: We found aberrantly high expression of EIF3B in pancreatic cancer, which associated with unfavorable prognosis. Knockdown of EIF3B greatly compromised cell viability and proliferation in both SW1990 and PANC-1 cells. Furthermore, EIF3B deficiency induced cell cycle arrest and spontaneous apoptosis. In vivo tumor progression was significantly suppressed by EIF3B silencing in the xenograft mouse model. Mechanistically, we characterized down-regulation of CDH1 and IRS1 and up-regulation of DDIT3, PTEN and CDKN1B, in response to EIF3B knockdown, which might mediate the oncogenic effect of EIF3B in pancreatic cancer. CONCLUSIONS: Our data uncovered the oncogenic role of EIF3B in pancreatic cancer.
Asunto(s)
Factor 3 de Iniciación Eucariótica , Neoplasias Pancreáticas , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Factor 3 de Iniciación Eucariótica/genética , Humanos , Ratones , Neoplasias Pancreáticas/genéticaRESUMEN
Peritoneal metastasis (PM) is the major cause of recurrence in patients with gastric cancer (GC) and is associated with poor prognosis. The oncogenic role of Nicotinamide N-methyltransferase (NNMT) in GC has been reported, but the role of secreted NNMT that is transported by exosomes remains unknown. In this study, exosomes were isolated from GC patients with or without PM and from GC cell line, including GC-114, GC-026, MKN45, and SNU-16 cells. The contents of NNMT were significantly enhanced in exosomes isolated from GC patients with PM compared with those from GC patients without PM. Furthermore, the levels of NNMT were significantly enhanced in exosomes from GC cell lines relative to those from normal human gastric epithelial cell line GES-1 cells. These data indicate that NNMT may be involved in intercellular communication for peritoneal dissemination. Moreover, colocalization of GC-derived exosomal NNMT was found in human peritoneal mesothelial cell line HMrSV5 cells. Additionally, relative to GES-1 exosomes, SNU-16 exosomes significantly activated TGF-ß/smad2 signaling in HMrSV5 cells. However, when NNMT was silenced, the activation of TGF-ß/smad2 by SNU-16 exosomes was abolished in HMrSV5 cells. We propose that NNMT-containing exosomes derived from GC cells could promote peritoneal metastasis via TGF-ß/smad2 signaling.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Nicotinamida N-Metiltransferasa/genética , Neoplasias Peritoneales/genética , Proteína Smad2/genética , Neoplasias Gástricas/genética , Factor de Crecimiento Transformador beta1/genética , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Supervivencia Celular , Exosomas/metabolismo , Exosomas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Nicotinamida N-Metiltransferasa/antagonistas & inhibidores , Nicotinamida N-Metiltransferasa/metabolismo , Neoplasias Peritoneales/metabolismo , Neoplasias Peritoneales/patología , Neoplasias Peritoneales/cirugía , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Proteína Smad2/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Peritoneal metastasis (PM) is the main cause of poor prognosis in patients with advanced gastric cancer (GC). Increasing evidence has suggested that cancer-associated EVs in body fluids may assist in the diagnosis and treatment of GC. Here, we investigated the role of GC-derived EVs in PM development. Our results demonstrate that expression of the tumor suppressor promyelocytic leukemia zinc finger (PLZF) is decreased in GC tissues and PM lesions from GC patients. PLZF suppression promoted migration and invasion of peritoneal mesothelial HMrSV5 cells, while PLZF overexpression suppressed HMrSV5 cell migration and invasion. Microarray analysis revealed significantly upregulated expression of several miRNAs in EVs isolated from GC patients with PM, including miR-544. The increased miR-544 expression was confirmed in GC tissues and PM-derived EVs. Transfection with miR-544 reduced PLZF expression in HMrSV5 cells, while miR-544 inhibition increased PLZF expression. Incubation of GC cells with peritoneal mesothelial HMrSV5 cells showed that miR-544 could be transferred from GC-derived EVs to peritoneal cells, where it suppressed the PLZF expression. These findings indicate that EV-mediated transfer of miR-544 decreases the PLZF expression in PM lesions, which suggests miR-544 could potentially serve as a diagnostic biomarker and therapeutic target for treatment of GC patients.