RESUMEN
Dysregulated actin cytoskeleton gives rise to aberrant cell motility and metastatic spread of tumor cells. The MRTF-SRF transcriptional complex plays a key role in regulating the expressions of actin cytoskeleton-modulatory genes. In this study, we demonstrate that MRTF's interaction with SRF is critical for migration and invasion of breast cancer cells. Disruption of the MRTF-SRF interaction suppresses membrane dynamics affecting the frequency and the effectiveness of membrane protrusion during cell motility. Consistent with these phenotypic changes, we further show that MRTF promotes actin polymerization at the leading edge, a key aspect of membrane protrusion, and migration of breast cancer cells through upregulating the expression of formin-family actin nucleating/elongating protein encoding gene DIAPH3 in an SRF-dependent manner. In support of these findings, multiplexed quantitative immunohistochemistry and transcriptome analyses of clinical specimens of breast cancer further demonstrate a positive correlation between nuclear localization of MRTF with malignant traits of cancer cells as well as enrichment of MRTF/SRF gene signature in distant metastases relative to primary tumors. In conclusion, this study for the first time links the MRTF/SRF signaling axis to cell migration through the regulation of a specific actin-binding protein, and provides evidence for an association between MRTF/SRF activity and malignancy in human breast cancer.
RESUMEN
BACKGROUND: Rates of adolescent obesity and overweight are high. The offspring of overweight parents are at increased risk of becoming obese later in life. Investigating neural correlates of familial obesity risk and current overweight status in adolescence could help identify biomarkers that predict future obesity and that may serve as novel targets for obesity interventions. OBJECTIVE: Our primary aim was to use functional MRI to compare neural responses to words denoting high or low energy density (ED) foods and non-foods, in currently lean adolescents at higher compared with lower familial risk for obesity, and in overweight compared with lean adolescents. Secondary aims were to assess group differences in subjective appetite when viewing food and non-food words, and in objective ad libitum intake of high-ED foods in a laboratory setting. DESIGN: We recruited 36 adolescents (14-19y), of whom 10 were (obese/overweight "overweight"), 16 lean with obese/overweight mothers (lean high-risk, "lean-HR"), and 10 lean with lean mothers (lean low-risk, "lean-LR"). All underwent fMRI scanning while they viewed words representing high-ED foods, low-ED foods, or non-foods, and provided appetitive ratings in response to each word stimulus. They then consumed a multi-item ad libitum buffet meal. RESULTS: Food compared with non-food words activated a distributed emotion/reward system including insula and pregenual anterior cingulate cortex (ACC). Participants who were at increasing risk for obesity exhibited progressively weaker activation of an attentional/regulatory system including dorsolateral prefrontal cortex (PFC), dorsal ACC, and basal ganglia nuclei (activation was greatest in lean-LR, intermediate in lean-HR, and weakest in the overweight group). These group differences were most apparent for neural responses to high-compared with low-ED foods. Lean-HR (compared with lean-LR and overweight) adolescents reported greater desire for high-ED foods. Meal intake was greatest for the overweight, then lean-HR, then lean-LR groups. CONCLUSIONS: Adolescents at higher obesity risk exhibited reduced neural responses to high-ED food cues in a neural system that subserves attention and self-regulation. They also reported heightened appetitive responses to high-ED cues. Interventions that promote the capacity for self-regulation could prevent youth who have a familial predisposition for obesity from translating risk into reality.
