Role of tissue differentiation factors in endocrine tumorigenesis

编码menin的MEN1基因的种系突变易导致内分泌肿瘤，主要发生在甲状旁腺、垂体前叶和肠胰内分泌组织。我们研究了胰岛细胞肿瘤（胰岛素瘤）发病机制中menin缺失引起的组织特异性肿瘤发生的分子基础。组织特异性的原因可能是由于menin介导的一个或多个组织特异性因子的调节，例如那些在胚胎发生过程中控制分化的因子。因此，我们评估了menin的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&#946；细胞分化因子HLXB9 （Mnx-1）在menin丢失时转录后上调。HLXB9在menin存在的情况下导致MIN6胰岛素瘤细胞凋亡。因此，HLXB9的失调预测了胰岛素瘤中细胞增殖的可能机制，这可能是由于HLXB9的促凋亡活性在menin丢失时可能被阻断。这些发现促进了对诸如menin之类的普遍表达蛋白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HLXB9及其靶点在&#946；-细胞中的作用机制。我们还发现HLXB9被激酶GSK-3&#946；磷酸化，phospho-HLXB9和GSK-3&#946；在小鼠和人&#946；细胞肿瘤中均有表达，GSK-3&#946；抑制剂（如氯化锂）可降低小鼠&#946；细胞肿瘤细胞系的细胞增殖并延缓细胞周期进展。我们感兴趣的是探索氯化锂治疗小鼠MEN1模型是否会减少内分泌肿瘤的发生。我们目前正在研究HLXB9在散发性胰腺内分泌肿瘤中的作用，以及phospho-HLXB9促进肿瘤发生的分子机制。这些研究将深入了解HLXB9及其靶点在正常细胞和肿瘤细胞中的通路和作用。

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 the cause of the tissue-specificity 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, in MIN6 insulinoma β-cells. Thus, dysregulation of HLXB9 predicts a possible mechanism for β-cell proliferation in insulinomas resulting from the possible blockade of the pro-apoptotic activity of 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 (such as lithium chloride) reduced cell proliferation and delayed cell cycle progression of mouse β-cell tumor cell lines. We are interested in exploring whether lithium chloride treatment in the mouse model of MEN1 would reduce endocrine tumorigenesis. 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.