Malignant gliomas are the most common central nervous system tumors and the molecular mechanism driving their development and recurrence is still largely unknown, limiting the treatment of this disease. Here, we show that restoring the expression of miR-218, a microRNA commonly downregulated in glioma, dramatically reduces the migration, invasion, and proliferation of glioma cells. Quantitative reverse transcription PCR and Western blotting analysis revealed that expression of the stem cell-promoting oncogene Bmi1 was decreased after overexpression of miR-218 in glioma cells. Mechanistic investigations defined Bmi1 as a functional downstream target of miR-218 through which miR-218 ablated cell migration and proliferation. We documented that miR-218 also blocked the self-renewal of glioma stem-like cells, consistent with the suggested role of Bmi1 in stem cell growth. Finally, we showed that miR-218 regulated a broad range of genes involved in glioma cell development, including Wnt pathways that suppress glioma cell stem-like qualities. Taken together, our findings reveal miR-218 as a tumor suppressor that prevents migration, invasion, proliferation, and stemlike qualities in glioma cells. Cancer Res; 73(19); 6046-55. Ó2013 AACR.

The specific expression of CDH5 in GSCs may contribute to GSC-derived neovasculogenesis in glioblastoma multiforme, especially under hypoxic conditions, revealing novel tumorigenic mechanisms contributed by GSCs.

The protein deacetylase, sirtuin 1 (SIRT1), involved in regulating hepatic insulin sensitivity, shows circadian oscillation and regulates the circadian clock. Recent studies show that circadian misalignment leads to insulin resistance (IR); however, the underlying mechanisms are largely unknown. Here, we show that CLOCK and brain and muscle ARNT-like protein 1 (BMAL1), two core circadian transcription factors, are correlated with hepatic insulin sensitivity. Knockdown of CLOCK or BMAL1 induces hepatic IR, whereas their ectopic expression attenuates hepatic IR. Moreover, circadian change of insulin sensitivity is impaired in Clock mutant, liver-specific Bmal1 knockout (KO) or Sirt1 KO mice, and CLOCK and BMAL1 are required for hepatic circadian expression of SIRT1. Further studies show that CLOCK/BMAL1 binds to the SIRT1 promoter to enhance its expression and regulates hepatic insulin sensitivity by SIRT1. In addition, constant darkness-induced circadian misalignment in mice decreases hepatic BMAL1 and SIRT1 levels and induces IR, which can be dramatically reversed by resveratrol. Conclusion: These findings offer new insights for coordination of the circadian clock and metabolism in hepatocytes by circadian regulation of hepatic insulin sensitivity via CLOCK/BMAL1-dependent SIRT1 expression and provide a potential application of resveratrol for combating circadian misalignment-induced metabolic disorders. (HEPATOLOGY 2014;59:2196-2206 G rowing evidence shows that circadian rhythms regulate a wide variety of metabolic processes, 1,2 and numerous metabolites, including glucose and lipids, and some metabolism-related hormones, such as insulin, oscillate in a circadian manner in blood. [3][4][5] Epidemiological studies show that circadian misalignment increases the risk of a series of diseases, including obesity and type 2 diabetes. Type 2 diabetes is usually characterized by abnormal high blood glucose and insulin resistance (IR), because insulin target tissues, including the liver, respond inadequately to circulating insulin. Lifestyle factors, such as diets rich in fat and poor in dietary fiber, sedentary lifestyle, and depression, are common causes for IR. 6 Circadian misalignment, a characteristic of jet lag and shift work, has also been reported to induce IR in human. [7][8][9] Circadian misalignment in rats elevates blood glucose and insulin levels, suggesting development of IR. 10 Genetic disruption of clock genes perturbs metabolic functions of specific tissues in mice at distinct phases of the sleep/wake cycle.2,11,12 CLOCK and brain and muscle ARNT-like protein 1 (BMAL1), Abbreviations: Akt, protein kinase B; BMAL1, brain and muscle ARNT-like protein