gms | German Medical Science

Purpose: It remains unknown which factors can divert the choroidal melanocytes or uveal melanoma (UM) cells towards the malignant versus benign genotypes with monosomy-3 or Chromosome(Chr)-6 gain, respectively. Here, we analyzed the outcomes of hyperglycemia on the segregation of Chr3 and -6.

Methods: Cultures of UM cells that were generated from the primary tumors of two patients, choroidal melanocytes and Tenon fibroblasts that were obtained from control patients, and the UM cell lines 92.1 and OMM2.5 were incubated in normo- or hyperglycemic medium for 1 day and treated with the reversible mitotic inhibitor Nocodazole. Co-detection of proteins with Chr3 and -6 was performed by Immuno-FISH.

Results: Hyperglycemia induced the dislocation of Chr3 from the periphery towards the nuclear center in the choroidal melanocytes and UM cells during interphase and reduced the angle between the centromeres of Chr3 but not Chr6 during prometaphase in UM cells, together with the upregulation of Ki67. During the later mitotic phases, hyperglycemia promoted the asymmetric segregation of Chr3, doubling the incidence of monosomy-3 in the UM cells. In contrast, the Tenon fibroblasts underwent the reverse pattern, with Chr6 being more prone to missegregation under hyperglycemia.

Conclusions: Our findings provide the first evidence for the crucial influence of hyperglycemia on the chromosomal territories in a cell-type dependent manner, which favors the generation of monosomy-3 over the Chr6 gain in the UM cells. Prevention of hyperglycemia may therefore be a simple approach to maintain the dormancy of the UM cells by impeding the generation of monosomy-3.