RESUMEN
BACKGROUND: Endogenous hydrogen sulfide (H2S)-responsive theranostic agents have attracted extensive attention due to their specificity for colon cancer. However, the development of such agents with high enrichment in tumors and excellent photothermal performance remains challenging. RESULTS: We prepared hyaluronic acid (HA)-coated Bi-doped cuprous oxide (Bi:Cu2O@HA) via a one-pot method. The HA specifically targets colon cancer tumor cells to improve the enrichment of Bi:Cu2O@HA at tumor sites, while the doped Bi both enhances the photothermal performance of the H2S-triggered Cu2O and serves as an agent for tumor imaging. The results in this work demonstrated that the Bi:Cu2O@HA nanoparticles exhibit good biocompatibility, target colon cancer tumor cells, facilitate computed tomography imaging, and enhanced H2S-responsive photothermal therapy performance, resulting in an excellent therapeutic effect in colon cancer. CONCLUSIONS: The novel Bi:Cu2O@HA nanoparticles exhibit excellent tumor targeting and photothermal therapeutic effects, which provide new strategies and insights for colon cancer therapy.
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Neoplasias del Colon , Nanopartículas , Línea Celular Tumoral , Neoplasias del Colon/diagnóstico por imagen , Neoplasias del Colon/tratamiento farmacológico , Humanos , Ácido Hialurónico , FototerapiaRESUMEN
BACKGROUND: Pancreatic cancer is one of the most lethal cancers worldwide. The aim of this study was to determine the expression pattern, clinical significance, and biological functions of Wnt5a in pancreatic cancer. METHODS: Immunohistochemistry was performed to examine Wnt5a expression in 134 surgically resected pancreatic adenocarcinoma and adjacent normal pancreatic tissues. Associations of Wnt5a expression with clinicopathological factors and cancer-specific survival were analyzed. The effects of Wnt5a overexpression or silencing on the invasiveness and epithelial-to-mesenchymal transition (EMT) of pancreatic cancer cells were studied. Silencing of ß-catenin by small interfering RNA was done to determine its role in the Wnt5a-mediated tumor phenotype. RESULTS: The percentage of Wnt5a positive expression showed a bell-shaped pattern in pancreatic cancer tissues, peaking in well-differentiated carcinomas. The median cancer-specific survival was comparable between patients with positive versus negative expression of Wnt5a. Overexpression of Wnt5a promoted the migration and invasion of pancreatic cancer cells, whereas Wnt5a depletion had an inhibitory effect. In an orthotopic pancreatic cancer mouse model, Wnt5a overexpression resulted in increased invasiveness and metastasis, coupled with induction of EMT in tumor cells. Treatment with recombinant Wnt5a elevated the nuclear ß-catenin level in pancreatic cancer cells, without altering the Ror2 expression. Targeted reduction of ß-catenin antagonized exogenous Wnt5a-induced EMT and invasiveness in pancreatic cancer cells. CONCLUSION: Upregulation of Wnt5a promotes EMT and metastasis in pancreatic cancer models, which involves activation of ß-catenin-dependent canonical Wnt signaling. These findings warrant further investigation of the clinical relevance of Wnt5 upregulation in pancreatic cancer.
Asunto(s)
Transición Epitelial-Mesenquimal , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Wnt/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patología , Adulto , Anciano , Línea Celular Tumoral , Movimiento Celular/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidad , Pronóstico , Proteínas Proto-Oncogénicas/genética , Transducción de Señal , Carga Tumoral , Proteínas Wnt/genética , Proteína Wnt-5a , beta Catenina/metabolismoRESUMEN
Wnt proteins are a group of secreted signaling proteins, which function to regulate cell fate and pattern formation during embryogenesis. Altered expression of Wnt5a has been implicated in human carcinogenesis and tumor progression. A previous study identified that Wnt5a is overexpressed in human pancreatic cancer tissues, and that upregulated expression of Wnt5a promotes tumor cell migration and invasion. The present study investigated the role of Wnt5a in pancreatic cancer cell proliferation in vitro and in an orthotopic nude mouse model. Wnt5a cDNA or small interfering RNA were stably transfected into pancreatic cancer cells to assess cell proliferation-associated behaviors, including cell viability, colony formation and apoptosis in vitro, as well as tumor cell growth in an orthotopic nude mouse model. Western blot analysis was used to analyze the expression of Wnt signaling molecules. The data showed that upregulation of the expression of Wnt5a significantly promoted proliferation of the human pancreatic cells, but inhibited tumor cell apoptosis in vitro and promoted tumor growth in an orthotopic nude mouse model. By contrast, knockdown of the expression of Wnt5a inhibited cell growth and promoted apoptosis of the pancreatic cancer cells. The data also revealed that ß-catenin mediated the effects of Wnt5a on the regulation of pancreatic cancer cell apoptosis in vitro. These results suggested that Wnt5a is involved in the modulation of pancreatic cancer cell proliferation, and that Wnt5a may be a potential target for pancreatic cancer therapy.
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Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas/metabolismo , Regulación hacia Arriba , Proteínas Wnt/metabolismo , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Modelos Animales de Enfermedad , Humanos , Inmunohistoquímica , Ratones Desnudos , Ensayo de Tumor de Célula Madre , Proteína Wnt-5a , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/metabolismoRESUMEN
OBJECTIVES: The aim of this study was to investigate the effect of the neurotrophic factor Artemin on neuroplasticity and perineural invasion of pancreatic adenocarcinoma. METHODS: Artemin expressions were detected in human pancreatic adenocarcinoma tissues by Western blot and immunohistochemistry. Artemin overexpression and RNA interference in the pancreatic cancer cell lines were performed to evaluate the effects of Artemin on cell proliferation, invasion, and neurotrophic activity in vitro and in nude orthotopic transplantation tumor models. RESULTS: Artemin expression in pancreatic cancer tissues was related to the incidence of lymphatic metastasis and perineural invasion as well as the mean density and total area of nerve fibers. Overexpression of Artemin in pancreatic cancer cell lines improved colony formation, cell migration, matrigel invasion, and neurotrophic activity in vitro. This overexpression also increased the volume of nude orthotopic transplantation tumors; promoted cancer cell invasion of the peripheral organs, nerves, vessels, and lymph nodes; and stimulated the proliferation of peritumoral nerve fibers. Artemin depletion by RNA interference had an inhibitory effect mentioned previously. CONCLUSIONS: Artemin could promote invasiveness and neurotrophic function of pancreatic adenocarcinoma in vivo and in vitro. Therefore, Artemin could be used as a new therapeutic target of pancreatic carcinoma.