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。组织特异性的原因可能是由于menin介导的一种或多种组织特异性因子的调节，例如那些在胚胎发生期间控制分化的因子。因此，我们评估了menin缺失或获得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（Mnx-1）是转录后上调后menin损失。HLXB 9在menin存在下引起细胞凋亡，并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联合机制。这可能是由于menin缺失时HLXB 9的促凋亡活性可能被阻断，以及menin缺失时HLXB 9增加导致胰岛素增加。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。我们还发现，HLXB 9被激酶GSK-3磷酸化，磷酸化HLXB 9和GSK-3在小鼠和人细胞肿瘤中表达，GSK-3抑制剂降低了小鼠细胞肿瘤细胞系的细胞增殖并延迟了细胞周期进程。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，以及磷酸化HLXB 9促进肿瘤发生的分子机制。这些研究将提供对HLXB 9及其靶点在正常细胞和细胞内肿瘤中的通路和作用的深入了解。

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.