Role of extracellular matrix and microenvironment in regulation of tumor growth and LAR-mediated invasion in glioblastoma
(A) Proposed role of miR-451 in the regulation of LKB1/AMPK-mTOR signaling in response to high and low glucose levels. miR-451 levels determine glioma cell migration or proliferation in response to glucose (triangle on the left) via the AMPK-mTOR network . Glucose withdrawal reduces miR-451 levels, resulting in up-regulation of AMPK activity and down-regulation of mTOR. This leads to reduced cell proliferation and enhanced cell motility. Normal glucose levels up-regulate miR-451, which leads to down-regulation of AMPK activity. In turn, down-regulated AMPK levels induce up-regulation of mTOR, which leads to increased proliferation and decreased cell migration. (B) Schematic components of miR-451, CAB39/LKB1/AMPK complex, and mTOR are represented by modules ‘M’ (dotted box on the left), ‘A’ (box with solid line in the middle), and ‘R’ (dotted box on the right), respectively, in our theoretical framework. (C) Detailed schematic of cellular decision of cell proliferation and migration in glioblastoma via signaling networks including miR-451, AMPK, mTOR, and players in the cell cycle module (CycB, Cdh1, p55cdcT, p55cdcA, Plk1) .