Role of tissue differentiation factors in endocrine tumorigenesis

编码menin的MEN 1基因的种系突变易患主要发生在甲状旁腺、垂体前叶和肠胰腺内分泌组织的内分泌肿瘤。我们已经研究了这种组织特异性肿瘤发生的分子基础，这种组织特异性肿瘤发生来自胰岛细胞肿瘤（胰岛素瘤）发病机制中的menin缺失。menin可能调节一种或多种组织特异性因子，例如在胚胎发生期间控制分化的因子。因此，我们评估了menin缺失或增加对已知控制细胞分化的因子表达的影响。我们发现，细胞分化因子Hlxb 9是转录后上调后menin损失。hlxb 9在menin存在下引起细胞凋亡，并且它调节调节胰岛素水平的基因。因此，Hlxb 9的失调预测了胰岛素瘤中细胞增殖和组成性胰岛素产生的可能的联合机制。这可能是由于在menin损失时Hlxb 9的促凋亡活性的可能阻断，以及在menin损失时Hlxb 9增加导致的胰岛素增加。这些发现推进了对一种普遍表达的蛋白质如menin如何控制组织特异性肿瘤发生的理解。此外，我们的数据揭示了Hlxb 9及其靶点在细胞中的作用机制。我们目前正在研究Hlxb 9在散发性胰腺内分泌肿瘤中的作用，以及menin-Hlxb 9联合促进细胞凋亡的分子机制。这些研究将深入了解Hlxb 9及其靶点在正常细胞和细胞内肿瘤中的途径和作用。

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 menin regulates 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 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 are currently investigating the role of Hlxb9 in sporadic pancreatic endocrine tumors, and the molecular mechanisms by which the menin-Hlxb9 association promotes apoptosis. These studies will provide insights into the pathways and actions of Hlxb9 and its targets in normal β-cells and in β-cell tumors.