Alterations in gene expression in MEN1-associated insulinoma development

Objectives: To identify gene expression alterations associated with insulinoma formation and progression in 2 mouse models of multiple endocrine neoplasia type 1. Methods: Mice were killed at 12 or 16 months, and pancreatic islets were isolated by enzymatic and physical disruption. Islets were separated by size representing control, normal, hyperplastic, and adenomous islets. RNA was isolated from these islets and profiled on Sentrix Mouse-6 Expression version 1 BeadChips. Array data were analyzed in GeneSpring. Results: One hundred and one genes that were significantly (P ≤ 0.05) altered in hyperplastic islets and insulinomas compared with normal islets were identified. Of these, 64 gene elements showed reduced messenger RNA levels and 37 gene elements had increased gene expression compared with control islets. Altered expression of 3 genes, namely, Gata6, Tspan8, and s100a8, was confirmed by quantitative reverse transcription-polymerase chain reaction, and aberrant levels of Tspan8 and Lmo2 protein measured by Western blot correlated with the changes in messenger RNA levels. Conclusions: These results suggest that alterations in gene expression of Gata6, Tspan8, S100a8, and Lmo2 may act via novel pathways that play functionally important roles in Men1-associated tumor progression.