RESUMO
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is widely prevalent in Taiwan, and high metastatic spread of ESCC leads to poor survival rate. Fibronectin (FN) assembly on the cell membrane may induce ESCC mobility. MicroRNAs (MiRNAs) are abundant in and participate in tumorigenesis in many cancers. However, the role of MiRNA in FN assembly-related ESCC mobility remains unexplored. METHODS: We divided ESCC CE81T cells into high-FN assembly (CE81FN+) and low-FN assembly (CE81FN-) groups by flow cytometry. MiRNA microarray analysis identified miR-146a expression as the most down-regulated miRNA in comparison of CE81FN+ and CE81FN- cells. RESULTS: Cell proliferation and migration were decreased when CE81FN+ cells overexpressed transgenic miR-146a compared to the parental cells, indicating an inverse correlation between low miR-146a expression and high proliferation as well as motility of FN assembly ESCC cells. Furthermore, vimentin is the target gene of miR-146a involved in ESCC tumorigenesis. MiR-146a suppressed cell proliferation, migration and invasion of CE81FN+ cells through the inhibition of vimentin expression, as confirmed by real-time PCR, Western blotting and Transwell™ assay. Analysis of one hundred and thirty-six paired ESCC patient specimens revealed that low miR-146a and high vimentin levels were frequently detected in tumor, and that the former was associated with late tumor stages (III and IV). Notably, either low miR-146a expression or high vimentin level was significantly associated with poor overall survival rate among ESCC patients. CONCLUSIONS: This is the first report to link FN assembly in the cell membrane with miR-146a, vimentin and ESCC tumorigenesis both in vitro and in ESCC patients.
Assuntos
Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Fibronectinas/genética , MicroRNAs/genética , Vimentina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Membrana Celular/fisiologia , Movimento Celular , Proliferação de Células , Neoplasias Esofágicas/etiologia , Carcinoma de Células Escamosas do Esôfago/etiologia , Feminino , Fibronectinas/metabolismo , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Vimentina/metabolismoRESUMO
OBJECTIVES: We sought to investigate the effects of time-restricted feeding (TRF) and a traditional weight-loss method on body composition and cardio-metabolic risk factors in middle-aged women. METHODS: In a single-center, randomized, open-label, parallel-group design, women ages 40 to 65 y with body mass index ≥ 24 kg/m2 or waist circumference > 80 cm were recruited. They were guided to a daily low-calorie diet of 1400 kcal and randomly assigned into a TRF group (limit 8 h of eating time and fasting for 16 h) or a non-TRF group (traditional weight-loss method, unrestricted eating time) for 8 wk. Body composition, blood pressure, blood biochemical variables, and insulin resistance status were measured before and after intervention. RESULTS: Body weight, body mass index, waist circumference, and body fat mass decreased significantly in both groups after 8 wk of intervention (P < 0.05). Body weight decreased more in the TRF group than the non-TRF group (-4.1% ± 2.8% versus -2.4% ± 2.5%; P = 0.012), as did diastolic blood pressure (75.3 ± 11.2 mm Hg versus 70.5 ± 9.4 mm Hg; P = 0.012). There were no statistical differences between the two groups in total cholesterol, triacylglycerols, high- or low-density lipoprotein cholesterol, and fasting insulin level. However, fasting glucose and insulin resistance status increased significantly for the TRF group after the intervention (respectively, 88.3 ± 7.6 mg/dL versus 92.6 ± 9.6 mg/dL, P = 0.003; 1.7 ± 0.7 versus 2.1 ± 1.0, P = 0.048). CONCLUSION: The weight loss and reduction in diastolic blood pressure using the TRF method were better than with the traditional weight-loss method. However, this method may increase fasting glucose levels and adverse insulin resistance status.
Assuntos
Composição Corporal , Jejum , Adulto , Idoso , Índice de Massa Corporal , Peso Corporal , Feminino , Humanos , Pessoa de Meia-Idade , TaiwanRESUMO
Homodimerization of RON (MST1R), a receptor tyrosine kinase, usually occurs in cells stimulated by a ligand and leads to the downstream activation of signaling pathways. Here we report that bladder cancer cells, in response to physiological stress, use an alternative mechanism for signaling activation. Time-course studies indicated that RON migrated directly from the membrane to the nucleus of bladder cancer cells in response to serum starvation. Biochemical and genetic studies implied that this nuclear internalization was complexed with epidermal growth factor receptor (EGFR) and required the docking of importins. In vivo analysis confirmed that nuclear RON was present in 38.4% (28/73) of primary bladder tumors. Chromatin immunoprecipitation (ChIP) on microarray analysis further revealed that this internalized complex bound to at least 134 target genes known to participate in three stress-responsive networks: p53, stress-activated protein kinase/c-jun N-terminal kinase and phosphatidylinositol 3-kinase/Akt. These findings suggest that RON, in a complex with EGFR, acts as a transcriptional regulator in response to acute disturbances (e.g. serum starvation) imposed on cancer cells. In an attempt to re-establish homeostasis, these cells bypass regular mechanisms required by ligand stimulation and trigger the RON-directed transcriptional response, which confers a survival advantage.