Missegregation of Chromosome 3 and Generation of Monosomy 3 in the Proliferating Uveal Melanoma Cells Under Hyperglycemia.

Purpose: In uveal melanoma (UM), coexistence of the fatal monosomy 3 with the benign gain of chromosome 6p occurs rarely. The spatial organization of chromosomes can be influenced by the nucleoli, which become larger under hyperglycemia. We therefore hypothesized that hyperglycemia may be responsible for chromosome-specific aberrations in UM and analyzed its effect on nucleolar organization, chromosome territories, and missegregation rates in vitro. Methods: UM cell lines 92.1 and OMM2.5, UM cells from the primary tumors of two patients, and Tenon fibroblasts from a control were incubated in normo- or hyperglycemic medium (with 5.5 or 25 mM glucose, respectively) for one day, followed by the mitotic arrest with Nocodazole for 18-24 hours and recovery in fresh medium. Co-detection of proteins with the centromeres of chromosomes 3 and 6 was performed by two-dimensional immunofluorescent in situ hybridization. Results: In the UM cells undergoing interphase, hyperglycemia promoted the dislocation of chromosome 3 toward the center along with nucleolar growth. During prometaphase, the mean angle between the centromeres of chromosome 3 was reduced below 90° under hyperglycemia (P = 0.02). During the later mitotic phases, hyperglycemia resulted in a 3.8-fold increase in the missegregation rate of chromosome 3 in UM cells (P < 0.001), whereas chromosome 6 rather than 3 was more prone to missegregation in the normoglycemic UM cells and hyperglycemic Tenon fibroblasts. Conclusions: Hyperglycemia can favor chromosome-specific aneuploidies by altering chromosome territories in a cell-type dependent manner. Prevention of hyperglycemia may be a simple therapeutic approach to impede the generation of monosomy 3 in UM.