RESUMEN
Periostin actively contributes to tissue injury, fibrosis, atherosclerosis, and inflammatory diseases; however, its role in hepatic fibrosis is unclear. Herein, we revealed that periostin expression was significantly up-regulated in carbon tetrachloride- and bile duct ligation-induced mice with acute and chronic liver fibrosis. Deficiency in periostin abrogated the development of liver fibrosis in mice. Carbon tetrachloride treatment significantly increased α-smooth muscle actin, fibronectin, and collagen I levels in wild-type mice, which were unaffected in periostin-knockout mice. Periostin-deficient mice showed a significantly reduced area of collagen deposition and decreased levels of serum alanine aminotransferase and aspartate aminotransferase compared with wild-type mice after 2 weeks of carbon tetrachloride administration. Chemokine ligand 2, IL-6, IL-1ß, tumor necrosis factor-α, and tissue inhibitor of metalloproteinases 1 mRNA levels were significantly lower in periostin-deficient mice than in wild-type mice after carbon tetrachloride treatment. Periostin colocalized with hepatic stellate cell-derived collagen I and α-smooth muscle actin in mouse acute and chronic fibrotic liver tissues. Transforming growth factor (TGF)-ß1 markedly induced periostin expression in primary mouse hepatic stellate cells. Periostin-deficient mice showed significantly lower levels of TGF-ß1 and TGF-ß2 compared with wild-type mice after carbon tetrachloride treatment. High levels of periostin in patients with acute or chronic hepatitis correlated with TGF-ß1 and TGF-ß2 expression in serum from patients with hepatitis. Data indicate that periostin is a novel mediator of hepatic fibrosis development.
Asunto(s)
Moléculas de Adhesión Celular/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Hepatitis/metabolismo , Inflamación/metabolismo , Cirrosis Hepática/metabolismo , Hígado/metabolismo , Animales , Moléculas de Adhesión Celular/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Colágeno/metabolismo , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Hepatitis/patología , Humanos , Inflamación/patología , Hígado/patología , Cirrosis Hepática/patología , Ratones , Ratones Noqueados , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
miR-543 has been implicated as having a critical role in the development of breast cancer, endometrial cancer and hepatocellular carcinoma. However, the exact clinical significance and biological functions of miR-543 in colorectal cancer (CRC) remain unclear. Here, we found that miR-543 expression significantly downregulated in tumors from patients with CRC, APCMin mice and a mouse model of colitis-associated colon cancer. miR-543 level was inversely correlated with the metastatic status of patients with CRC and the metastatic potential of CRC cell lines. Moreover, ectopic expression of miR-543 inhibited the proliferation and metastasis of CRC cells in vitro and in vivo by targeting KRAS, MTA1 and HMGA2. Conversely, miR-543 knockdown promoted the proliferation, migration and invasion of CRC cells in vitro and augmented tumor growth and metastasis in vivo. Furthermore, we found that miR-543 expression was negatively correlated with the levels of KRAS, MTA1 and HMGA2 in clinical samples. Collectively, these data show that miR-543 inhibits the proliferation and metastasis of CRC cells by targeting KRAS, MTA1 and HMGA2. Our study highlights a pivotal role for miR-543 as a suppressor in the regulation of CRC growth and metastasis and suggests that miR-543 may serve as a novel diagnostic and prognostic biomarker for CRC metastasis.
Asunto(s)
Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica , Proteína HMGA2/genética , Histona Desacetilasas/genética , MicroARNs/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Represoras/genética , Regiones no Traducidas 3'/genética , Animales , Células CACO-2 , Línea Celular Tumoral , Proliferación Celular/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Femenino , Células HCT116 , Células HEK293 , Proteína HMGA2/metabolismo , Células HT29 , Histona Desacetilasas/metabolismo , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Desnudos , Persona de Mediana Edad , Metástasis de la Neoplasia , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteínas Represoras/metabolismo , Transactivadores , Trasplante Heterólogo , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genéticaRESUMEN
Aberrant changes in specific glycans have been shown to be associated with immunosurveillance, tumorigenesis, tumor progression and metastasis. In this study, the N-glycan profiling of membrane proteins from human breast cancer cell lines and tissues was detected using modified DNA sequencer-assisted fluorophore-assisted carbohydrate electrophoresis (DSA-FACE). The N-glycan profiles of membrane proteins were analyzed from 7 breast cancer cell lines and MCF 10A, as well as from 100 pairs of breast cancer and corresponding adjacent tissues. The results showed that, compared with the matched adjacent normal tissue samples, two biantennary N-glycans (NA2 and NA2FB) were significantly decreased (p <0.0001) in the breast cancer tissue samples, while the triantennary glycan (NA3FB) and a high-mannose glycan (M8) were dramatically increased (p = 0.001 and p <0.0001, respectively). Moreover, the alterations in these specific N-glycans occurred through the oncogenesis and progression of breast cancer. These results suggested that the modified method based on DSA-FACE is a high-throughput detection technology that is suited for analyzing cell surface N-glycans. These cell surface-specific N-glycans may be helpful in recognizing the mechanisms of tumor cell immunologic escape and could be potential targets for new breast cancer drugs.