RESUMEN
Colorectal cancer (CRC) is a common malignant tumor of digestive tract, but the molecular mechanism of its occurrence and development is not clear. Some studies have shown that microRNA (miRNA) plays an important role in the occurrence and development of cancer, but many miRNAs which play an important role in the progression of CRC remain to be investigated. In this studyï¼we found that the expression of miR-1538 was significantly down-regulated in CRC tissues and cells, and its expression level was significantly correlated with tumor size, clinical stage and prognosis. Functional and mechanism experiments showed that miR-1538 decreased the protein level of DNA methyltransferases 3A (DNMT3A) and inhibited the proliferation, migration and invasion of CRC cells by targeting the 3'-UTR of DNMT3A mRNA. Our results identify the biological function and mechanism of miR-1538 as a tumor suppressor gene in the progression of CRC, and suggest that miR-1538 can be used as a potential prognostic marker and therapeutic target for CRC.
Asunto(s)
Neoplasias Colorrectales , MicroARNs , Humanos , Regiones no Traducidas 3'/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Neoplasias Colorrectales/patología , ADN Metiltransferasa 3A , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
Liver cancer is a worldwide disease, and, currently, due to the poor prognostic and therapeutic options of liver cancer, we investigated the T cell epitopes as potential therapeutic vaccine candidates to get the benefit of experimental processes and utilize the complete ability of the immune system compared with other artificial ex vivo proliferation of T cells. Activation of T cells targets and kills several tumors, developing a strong rationale for the improvement of immunotherapeutic strategies to cancer therapy. To predict T cell epitopes for liver cancer, we designed a comprehensive immunoinformatics framework involving data mining, immunogenicity prediction, functional proteomic analysis, conservation studies, molecular modeling, and in vivo validation analysis. We found the binding affinity of antigenic peptides with major histocompatibility complex (MHC) I molecules to control the cancerous activity. Five extracellular antigenic proteins, including complement protein (C6), serotransferrin, coagulation factor XIII B, serum albumin (ALB), and prothrombin, were identified. We predicted and synthesized T cell epitopes to human leukocytes antigen-A*01:01 allele of MHC class I molecule. The hematological assay and IgG ELISA showed that C6 and ALB epitopes induced the production of lymphocytes, granulocytes, and peptide-specific IgG in immunized rats. We observed substantial high levels of granzymes B in serum samples of C6 and ALB compared with control, indicating the activity of cytotoxic T cells. We concluded that C6 and ALB are likely to contain potential epitopes for the induction of protective effector molecules, supporting the feasibility of therapeutic peptide-based vaccine for liver cancer.NEW & NOTEWORTHY We observed substantial high levels of granzymes B in serum samples of component C6 (C6) and albumin (ALB) compared with control, indicating the activity of cytotoxic T cells. We concluded that C6 and ALB are likely to contain potential epitopes for the induction of protective effector molecules, supporting the feasibility of therapeutic peptide-based vaccine for liver cancer.
Asunto(s)
Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Epítopos de Linfocito T/inmunología , Neoplasias Hepáticas/prevención & control , Proteínas de Neoplasias/inmunología , Animales , Biología Computacional , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/terapia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Mapas de Interacción de Proteínas , Proteómica , RatasRESUMEN
Pancreatic cancer (PC) is predominantly incurable and is primarily treated with gemcitabine, but drug resistance commonly develops. Thus, new medicines are needed. Ceritinib (LDK378) is a second-generation tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) with antitumor activity in various cancers. However, studies involving ceritinib for the treatment of PC are inadequate. We analyzed the combined effects of ceritinib and gemcitabine on PC and their mechanism of action. Three PC cell lines were used to evaluate the antitumor effects of ceritinib combined with gemcitabine. We analyzed cell viability using CCK-8 assays, determined apoptosis levels through flow cytometry, and analyzed autophagy and cell signaling pathways by Western blotting and tissue array analysis with samples from xenograft models. Ceritinib strongly inhibited the proliferation of PC cells in a dose-dependent manner, induced apoptosis, and inhibited autophagy and cell migration by regulating relevant factors. Ceritinib in combination with gemcitabine exhibited significant growth inhibition and additive antitumor effects in vitro. In vivo, gemcitabine and ceritinib reduced tumor size by up to 30%. In our study, ALK was shown to be highly expressed in various PC cells and tissues. Ceritinib strongly inhibited the levels of activated ALK in PC cells with subsequent effects on the downstream mediators STAT3, AKT, and ERK. In addition, ceritinib inhibited tumor progression in xenograft models. Overall, our research shows that ceritinib inhibits the ALK signaling pathway, leading to cell growth/angiogenesis inhibition in PC and the induction of apoptosis. We recommend using ceritinib as a new treatment for PC.NEW & NOTEWORTHY These data proved that ceritinib inhibits the anaplastic lymphoma kinase signaling pathway, leading to cell growth/angiogenesis inhibition and the induction of apoptosis by inhibiting STAT3, AKT, and ERK pathway in pancreatic cancer (PC). We recommend using ceritinib as a new treatment for PC.
Asunto(s)
Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Sulfonas/farmacología , Quinasa de Linfoma Anaplásico/metabolismo , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Tamaño de la Célula/efectos de los fármacos , Desoxicitidina/farmacología , Resistencia a Antineoplásicos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
Severe acute pancreatitis (SAP) has a complex course and a worse prognosis. Immune response imbalance is an important cause of severe pancreatitis or even death in patients. Immunomodulation therapy can regulate the imbalance of inflammatory response, alleviate SAP-related organ damage and improve the prognosis of patients. There are some problems in early immune regulation measures, such as single target and simple way. In recent years, new treatment methods, such as regulating the maturation and apoptosis of immune cells, the application of mesenchymal stem cells (MSCs) and multifactor combination therapy, have provided new ideas and hope for the future treatment of SAP. This article reviews the development of SAP immunoregulation and its recent progress.
Asunto(s)
Inmunomodulación , Células Madre Mesenquimatosas/inmunología , Pancreatitis/tratamiento farmacológico , Pancreatitis/inmunología , Animales , Citocinas/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Humanos , Inflamación/inmunología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Madre Mesenquimatosas/metabolismo , Pancreatitis/metabolismo , Pancreatitis/terapia , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
Acute pancreatitis (AP) is an acute gastrointestinal disorder that is the most common and requiring emergency hospitalization. Its incidence is increasing worldwide, thus increasing the burden of medical services. Approximately 20% of the patients develop moderate to severe necrotizing pancreatitis associated with pancreatic or peri-pancreatic tissue necrosis and multiple organ failure. There are many reports about the anti-inflammatory effect of mesenchymal stem cells (MSCs) on pancreatitis and the repair of tissue damage. MSCs cells come from a wide range of sources, autologous MSCs come from bone marrow and allogeneic MSCs such as umbilical cord blood MSCs, placenta-derived MSCs, etc. The wide source is not only an advantage of MSCs but also a disadvantage of MSCs. Because of different cell sources and different methods of collection and preparation, it is impossible to establish a unified standard method for evaluation of efficacy. The biggest advantage of iMSCs is that it can be prepared by a standardized process, and can be prepared on a large scale, which makes it easier to commercialize. This paper reviews the present status of diagnosis and progress of MSCs therapy for AP.
Asunto(s)
Trasplante de Células Madre Mesenquimatosas , Pancreatitis/diagnóstico , Pancreatitis/terapia , Animales , Humanos , Mediadores de Inflamación , Pancreatitis/fisiopatología , Resultado del TratamientoRESUMEN
Severe acute pancreatitis (SAP) is an inflammatory disorder that progresses with local and systemic difficulties accompanied by a relatively high mortality rate. In recent years, maresin 1 (MaR1) has been shown to be a macrophage mediator with effective proresolving and anti-inflammatory properties that prevents the occurrence of various inflammatory conditions. The purpose of this study was to investigate the role of MaR1 in SAP and related lung injury. Experimental SAP was induced in mice with a combination of cerulean and lipopolysaccharide. MaR1 was administered 30 min before the primary injection of cerulean. Biochemical markers and histological injury scores were used to evaluate the severity of acute pancreatitis. To determine the degree of inflammation, serum cytokines and myeloperoxidase activity in pancreas and lung tissues were measured. Western blot analysis detected the activation of NF-κB. After MaR1 pretreatment, the activities of amylase, lipase, TNF-α, IL-1ß, and IL-6 were decreased in serum, and the myeloperoxidase activity both in pancreas and in lung tissues significantly decreased, whereas the activity of anti-inflammatory cytokine IL-10 in serum was increased. MaR1-pretreated mice reduced the activation of pancreatic NF-κB and decreased the severity of pancreatic and lung-related injuries. These results confirm that MaR1 alleviated inflammation of the pancreas and lung by inhibiting the activity of NF-κB in experimentally induced acute pancreatitis and exerted anti-inflammatory effects. These findings suggest that MaR1 could be a new and useful drug in the treatment of SAP.NEW & NOTEWORTHY These results provided us evidence to confirm that maresin 1 (MaR1) can alleviate inflammation of the pancreas and lung by inhibiting the activity of NF-κB in experimental induced acute pancreatitis and exerts certain anti-inflammatory effects. These findings suggest that MaR1 could be a new and useful drug in the treatment of severe acute pancreatitis.