RESUMEN
The rapid proliferative biological behavior of primary foci of anaplastic thyroid cancer (ATC) makes it a lethal tumor. According to the specific iodine uptake capacity of thyroid cells and enhanced endocytosis of ATC cells, we designed a kind of nanoclay drug-loading system and showed a promising treatment strategy for ATC. Introducing potassium iodide (KI) improves the homoaggregation of clay nanoparticles and then affects the distribution of nanoparticles in vivo, which makes KI@DOX-KaolinMeOH enriched almost exclusively in thyroid tissue. Simultaneously, the improvement of dispersibility of KI@DOX-KaolinMeOH changes the target uptake of ATC cells by improving the endocytosis and nanoparticle-induced autophagy, which regulate the production of autolysosomes and autophagy-enhanced chemotherapy, eventually contributing to a tumor inhibition rate of more than 90% in the primary foci of ATC. Therefore, this facile strategy to improve the homoaggregation of nanoclay by introducing KI has the potential to become an advanced drug delivery vehicle in ATC treatment.
Asunto(s)
Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Yoduro de Potasio/farmacología , Yoduro de Potasio/uso terapéutico , Caolín , Endocitosis , Sistemas de Liberación de Medicamentos , Neoplasias de la Tiroides/tratamiento farmacológicoRESUMEN
BACKGROUND: CD147 contributes to increased aerobic glycolysis through which it promotes tumor growth. Accumulating evidence suggests that CD147 exerts a variety of functions in thyroid cancer (TC) progression but the molecular mechanisms and therapeutic value of CD147 remain unclear. METHODS: CD147 levels in TC tissues were analyzed to assess its relationship with prognosis and disease progression. A microRNA (miRNA) microarray and bioinformatics approach were used to identify microRNA regulators of CD147 through measurement of the expression and functions of these miRNAs in TC tissues and cell lines. Precursor miRNA-transfected cells were used to assess regulation of CD147 by miRNA. The effect of miRNA on TC cells via inhibition of glycolysis through CD147 targeting was also evaluated. RESULTS: We found that miR-125a-5p regulates CD147 and is negatively correlated with its expression and function. Moreover, CD147 knockdown or increased miR-125a-5p expression significantly reduced the viability, migration, and invasion of TC cells. Our mechanistic studies demonstrate that, through directly repressing the expression of the CD147 protein, miR-125a-5p suppresses aerobic glycolysis and lactate production and subsequently reduces TC cell viability, migration, and invasion, thereby exerting tumor suppressor functions. CONCLUSIONS: The novel connection identified between miR-125a-5p and CD147 suggests a new diagnostic and prognostic role for miR-125a-5p and that CD147 inhibition may be a candidate therapeutic target in the therapy of for TC.
Asunto(s)
Basigina/metabolismo , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Glucosa/metabolismo , MicroARNs/metabolismo , Neoplasias de la Tiroides/metabolismo , Adulto , Apoptosis/genética , Basigina/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Glucólisis/genética , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Pronóstico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patologíaRESUMEN
Abnormal metabolism of cholesterol may be a contributing factor in nonalcoholic steatohepatitis (NASH) pathogenesis. Accumulating evidence has shown that liver X receptor (LXR) is closely related to intrahepatic inflammation and fibrosis. In this study, we evaluated the effects of a novel liver-specific LXR inverse agonist, SR9243, on antifibrosis in NASH mice. A high-cholesterol diet was employed to induce NASH in BALB/c mice by either carbon tetrachloride (CCL4) administration or bile-duct ligation (BDL). Once NASH was induced, mice were treated with SR9243 for one month by intraperitoneal (i.p.) injection. Liver tissues were collected to determine the degree of fibrosis and intrahepatic inflammation via pathological examination and QPCR; serum was collected to analyze the plasma lipid levels and liver function by clinical biochemistry. The mice developed hepatic steatosis, severe hepatic inflammation, and fibrosis by BDL or CCL4. Treatment with SR9243 significantly reduced the severity of hepatic inflammation and ameliorated hepatic fibrosis; simultaneously, body weight, serum glucose, and plasma lipid levels were controlled effectively. Our data demonstrate that SR9243 exerts an antifibrotic and anti-inflammatory effect in NASH mice; hence these findings highly suggest that LXR inverse agonist could be therapeutically important in NASH treatment.
Asunto(s)
Inflamación/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Receptores X del Hígado/agonistas , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Animales , Conductos Biliares/patología , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Tetracloruro de Carbono , Citocinas/genética , Citocinas/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Inflamación/sangre , Inflamación/complicaciones , Inflamación/patología , Mediadores de Inflamación/metabolismo , Insulina/sangre , Ligadura , Lípidos/sangre , Hígado/efectos de los fármacos , Hígado/fisiopatología , Cirrosis Hepática/sangre , Cirrosis Hepática/complicaciones , Cirrosis Hepática/patología , Receptores X del Hígado/metabolismo , Masculino , Ratones Endogámicos BALB C , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Sulfonamidas/farmacologíaRESUMEN
This study was aimed to identify the prognostic risk markers for thyroid papillary carcinoma (TPC) by bioinformatics. The clinical data of TPC and their microRNAs (miRNAs) and genes expression profile data were downloaded from The Cancer Genome Atlas. Elastic net-Cox's proportional regression hazards model (EN-COX) was used to identify the prognostic associated factors. The receiver operating characteristic (ROC) curve and Kaplan-Meier (KM) curve were used to screen the significant prognostic risk miRNA and genes. Then, the target genes of the obtained miRNAs were predicted followed by function prediction. Finally, the significant risk genes were performed literature mining and function analysis. Total 1046 miRNAs and 20531 genes in 484 cases samples were identified after data preprocessing. From the EN-COX model, 30 prognostic risk factors were obtained. Based on the 30 risk factors, 3 miRNAs and 11 genes were identified from the ROC and KM curves. The target genes of miRNA-342 such as B-cell CLL/lymphoma 2 (BCL2) were mainly enriched in the biological process related to cellular metabolic process and Disease Ontology terms of lymphoma. The target genes of miRNA-93 were mainly enriched in the pathway of G1 phase. Among the 11 prognostic risk genes, v-maf avian musculoaponeurotic fibrosarcoma oncogene homologue F (MAFF), SRY (sex-determining region Y)-box 4 (SOX4), and retinoic acid receptor, alpha (RARA) encoded transcription factors. Besides, RARA was enriched in four pathways. These prognostic markers such as miRNA-93, miRNA-342, RARA, MAFF, SOX4, and BCL2 may be used as targets for TPC chemoprevention.