RESUMEN
PURPOSE: The proinflammatory cytokine interleukin-32 (IL-32) is a novel tumor marker highly expressed in various human carcinomas, including gastric cancer. However, its effects on prognosis of patients with gastric cancer and cancer metastasis are virtually unknown at present. The main aim of this study was to explore the clinical significance of IL-32 in gastric cancer and further elucidate the molecular mechanisms underlying IL-32-mediated migration and invasion. EXPERIMENTAL DESIGN: Gastric cancer cells with ectopic expression or silencing of IL-32 were examined to identify downstream molecules and establish their effects on cell motility, invasion, and lung metastasis in vivo. RESULTS: IL-32 was significantly upregulated in gastric cancer and positively correlated with aggressiveness of cancer and poor prognosis. Ectopic expression of IL-32 induced elongated morphology and increased cell migration and invasion via induction of IL-8, VEGF, matrix metalloproteinase 2 (MMP2), and MMP9 expression via phosphor-AKT/phospho-glycogen synthase kinase 3ß/active ß-catenin as well as hypoxia-inducible factor 1α (HIF-1α) signaling pathways. Conversely, depletion of IL-32 in gastric cancer cells reversed these effects and decreased lung colonization in vivo. Examination of gene expression datasets in oncomine and staining of gastric cancer specimens demonstrated the clinical significance of IL-32 and its downstream molecules by providing information on their coexpression patterns. CONCLUSIONS: IL-32 contributes to gastric cancer progression by increasing the metastatic potential resulting from AKT, ß-catenin, and HIF-1α activation. Our results clearly suggest that IL-32 is an important mediator for gastric cancer metastasis and independent prognostic predictor of gastric cancer.
Asunto(s)
Interleucinas/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Movimiento Celular/genética , Análisis por Conglomerados , Progresión de la Enfermedad , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Interleucina-8/metabolismo , Interleucinas/metabolismo , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Persona de Mediana Edad , Invasividad Neoplásica , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidad , Carga Tumoral , Factor A de Crecimiento Endotelial Vascular/metabolismo , beta Catenina/metabolismoRESUMEN
Thyroid hormone (T(3)) signaling through the thyroid hormone receptor (TRα1) regulates hepatoma cell growth and pathophysiology, but the underlying mechanisms are unclear at present. Here, we have shown that the oncomir microRNA-21 (miR-21) is activated by T(3) through a native T(3) response element in the primary miR-21 promoter. Overexpression of miR-21 promoted hepatoma cell migration and invasion, similar to that observed with T(3) stimulation in hepatoma cells. In addition, anti-miR-21-induced suppression of cell migration was rescued by T(3). The Rac-controlled regulator of invasion and metastasis, T-cell lymphoma invasion and metastasis 1 (TIAM1), was identified as a miR-21 target additionally downregulated by T(3). Attenuation and overexpression of miR-21 induced upregulation and downregulation of TIAM1, respectively. TIAM1 attenuation, in turn, enhanced migration and invasion via the upregulation of ß-catenin, vimentin, and matrix metalloproteinase-2 in hepatoma cells. Notably, correlations between TRα1, miR-21, and TIAM1 expression patterns in animal models paralleled those observed in vitro. In the clinic, we observed a positive correlation (P = 0.005) between the tumor/nontumor ratios of TRα1 and miR-21 expression, whereas a negative correlation (P = 0.019) was seen between miR-21 and TIAM1 expression in patients with hepatoma. Our findings collectively indicate that miR-21 stimulation by T(3) and subsequent TIAM1 suppression promotes hepatoma cell migration and invasion.
Asunto(s)
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , MicroARNs/genética , Hormonas Tiroideas/farmacología , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Orden Génico , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Células Hep G2 , Humanos , Masculino , Invasividad Neoplásica , Ratas , Receptores de Hormona Tiroidea/genética , Receptores de Hormona Tiroidea/metabolismo , Reproducibilidad de los Resultados , Elementos de Respuesta , Proteína 1 de Invasión e Inducción de Metástasis del Linfoma-T , Triyodotironina/farmacologíaRESUMEN
The thyroid hormone 3,3',5-triiodo-L-thyronine (T3) mediates several physiological processes, including embryonic development, cellular differentiation, metabolism, and the regulation of cell proliferation. Thyroid hormone receptors (TRs) generally act as heterodimers with the retinoid X receptor (RXR) to regulate target genes. In addition to their developmental and metabolic functions, TRs have been shown to play a tumor suppressor role, suggesting that their aberrant expression can lead to tumor transformation. Conversely, recent reports have shown an association between overexpression of wild-type TRs and tumor metastasis. Signaling crosstalk between T3/TR and other pathways or specific TR coregulators appear to affect tumor development. Since TR actions are complex as well as cell context-, tissue- and time-specific, aberrant expression of the various TR isoforms has different effects during diverse tumorigenesis. Therefore, elucidation of the T3/TR signaling mechanisms in cancers should facilitate the identification of novel therapeutic targets. This review provides a summary of recent studies focusing on the role of TRs in hepatocellular carcinomas (HCCs).