Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults that is currently incurable with an average survival of slightly more than one year past the initial diagnosis. Although significant progress has been made in understanding the genetic changes associated with the progression of GBM, much more needs to be learned before better treatment for this disease can be developed based on information gathered from analysis of molecular links between pathological features and prognostic consequences of patients. In this regard, we have examined changes in the expression profiles of microRNAs associated with responses to hypoxic conditions by CD133+ glioma stem/tumor initiating cells (GSCs). Our preliminary data indicated that a set of microRNAs exhibits significant alterations in their expression profile in response to hypoxic culturing conditions by the CD133+ GSCs, suggesting that they may play roles in the biological responses of these cells to the hypoxic stress. Furthermore, manipulation on the expression of a selected few miRNAs from this group led to significant changes in the xenograft growth of CD133+ GSCs inoculated into the intracranial environment in nude mice, as well as their growth and neurosphere formation in culture, indicating that those miRNAs modulate specific pathological activities of those cells. In the meantime, we have obtained evidence indicative of hypoxia-induced regulation of miRNA processing, uncovering new insights into the molecular nature of the signaling pathway by which hypoxia acts to elicit changes in miRNA expression profile. To further explore these findings, we propose three specific aims: 1. Continue the determination of the functional roles and acting mechanisms of a selected number of microRNAs whose expression is correlated with hypoxic response in GSCs. 2. Explore the roles of those identified miRNAs on tumor formation/progression using an established transgenic mouse model. 3. Examine the regulatory mechanisms that modulate miRNA processing by the Drosha complex in response to hypoxia in GSCs. We will employ both cell culture and mouse models to accomplish these objectives.
GBM is one of the most deadly malignancies with few effective therapies. This study will lay the foundation upon which better therapeutic approaches could be developed in the future.
|Wang, Hui; Sun, Tao; Hu, Jing et al. (2014) miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways. J Clin Invest 124:4489-502|