Role of tissue differentiation factors in endocrine tumorigenesis

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Germline mutations in the MEN1 gene encoding menin predispose to endocrine tumors mainly of the parathyroids, anterior pituitary and entero-pancreatic endocrine tissues. We have investigated the molecular basis of this tissue specific tumorigenesis from menin loss in the pathogenesis of tumors of the pancreatic islet β-cells (insulinoma). It is possible that the cause of the tissue-specificty is due to menin-mediated regulation of one or more tissue-specific factors such as those that control differentiation during embryogenesis. Therefore, we assessed the effect of menin loss or gain on the expression of factors that are known to control β-cell differentiation. We found that the β-cell differentiation factor HLXB9 (Mnx-1) is post-transcriptionally upregulated upon menin loss. HLXB9 causes apoptosis in the presence of menin, and it regulates genes that modulate insulin level. Thus, dysregulation of HLXB9 predicts a possible combined mechanism for β-cell proliferation and constitutive insulin production in insulinomas. This would result from the possible blockade of the pro-apoptotic activity of HLXB9 upon menin loss, and increased insulin from increased HLXB9 upon menin loss. These findings advance the understanding of how a ubiquitously expressed protein such as menin controls tissue-specific tumorigenesis. Moreover, our data reveal the mechanisms of action of HLXB9 and its targets in β-cells. We also showed that HLXB9 is phosphorylated by the kinase GSK-3β, both phospho-HLXB9 and GSK-3β are expressed in mouse and human β-cell tumors, and GSK-3β inhibitors reduced cell proliferation and delayed cell cycle progression of mouse β-cell tumor cell lines. We are currently investigating the role of HLXB9 in sporadic pancreatic endocrine tumors, and the molecular mechanisms by which phospho-HLXB9 promotes tumorigenesis. These studies will provide insights into the pathways and actions of HLXB9 and its targets in normal β-cells and in β-cell tumors.