NEURAL TRANSCRIPTION FACTOR IN LUNG CANCER EVOLUTION

描述(改编自调查人员的摘要)：这项拨款提案 重点是碱性螺旋-环-螺旋转录因子的作用，人类 脱毛同源基因-1(HASH1)对MOST细胞表型的调控作用 侵袭性和高转移性人肺肿瘤，小细胞肺 癌症(SCLC)。HASH1是一种人类版的果蝇 Ahaete-Scute复合体(AS-C)，一个保守的转录因子家族 对于原始神经前体细胞的承诺是必不可少的。 研究人员已经确定hASH1在肺癌中表达。 模式与神经内分泌表型的存在密切相关 包括经典的小细胞肺癌细胞。基因操作模仿一种 小细胞肺癌和非小细胞肺癌表型之间的转换导致小细胞肺癌灭绝 HASH1表达。鲍尔博士还展示了该基因在 正常胎儿肺内分泌细胞，聚集在神经上皮体中。 由于肺内分泌细胞是最先分化的细胞之一 在肺上皮发育过程中出现的类型，这是 表达模式将hASH1置于调节基本过程的位置 在肺发育和小细胞肺癌表型的建立上。一个 胎儿肺内分泌细胞和小细胞肺癌的特征都是 细胞成簇状、紧密组织、独立于锚定的聚集体。在……里面 果蝇神经系统发育，AS-C触发器的表达 聚集事件和细胞-细胞信号，导致出现 单个显性神经母细胞与毗邻区AS-C的下调 细胞，然后承担上皮性的命运。很多信号都是 参与这一侧向反应的分子和转录因子 现在已知抑制过程与哺乳动物同源；一个惊人的 功能同源性的程度现在也在出现。在一系列 转基因实验表明，外源基因的表达 在不表达该基因的肺癌细胞中，hASH1可以 在还原血清中诱导细胞在致密的漂浮聚集体中生长。是这样的 研究结果表明，hASH1可能对小细胞肺癌的表型至关重要， 包括它特有的聚集行为。建议的一系列 现在的研究试图确定：1)肺癌的神经内分泌特征 分化和生长，尤其与细胞的功能有关 旁分泌生长因子，可能受hASH1调控；2)分子 可能构成hASH1的表面黏附分子的事件和变化 肺癌中介导的细胞-细胞黏附；3)调控hASH1的途径 肺癌中的基因表达，强调进化保守 果蝇神经发生的因素；4)hASH1表达在果蝇神经发生中的作用 肺内分泌细胞在正常肺发育和对 实验性肺损伤。这些研究将提供一种强有力的方法来 了解SCLC的起源以及 将这种肿瘤与这种疾病的其他主要形式联系起来，可能 导致肺癌新的治疗靶点的发现。

DESCRIPTION (adapted from the investigator's abstract): This grant proposal focuses on the role of a basic-helix-loop-helix transcription factor, human achaete-scute homolog-1 (hASH1) in regulating the phenotype of the most aggressive and highly metastatic of human lung tumors, small cell lung carcinoma (SCLC). hASH1 is a human counterpart to the Drosophila achaete-scute complex (AS-C), a conserved family of transcription factors that are essential for the commitment of primitive neural precursor cells. The investigator has determined that hASH1 is expressed in lung cancers in a pattern tightly correlated with the presence of the neuroendocrine phenotype including classic SCLC cells. Genetic manipulations which mimic a transition between SCLC and non-SCLC phenotypes resulted in extinction of hASH1 expression. Dr. Ball has also demonstrated expression of the gene in normal fetal pulmonary endocrine cells, clustered in neuroepithelial bodies. Since pulmonary endocrine cells are among the first differentiated cell types to appear in development of the pulmonary airway epithelium, this expression pattern places hASH1 in a position to mediate essential processes in both lung development and establishment of the SCLC phenotype. A hallmark of both fetal pulmonary endocrine cells and SCLC is the growth of cells in clustered, tightly organized, anchorage-independent aggregates. In Drosophila nervous system development, expression of the AS-C triggers clustering events and cell-cell signaling which results in emergence of a single dominant neuroblast and down-regulation of the AS-C in adjoining cells, which then assume an epithelial fate. Many of the signaling molecules and transcription factors that participate in this lateral inhibition process are now known to have mammalian homologs; a striking degree of functional homology is also now emerging. In a series of transfections experiments, they have shown that exogenous expression of hASH1 in lung cancer cells which do not endogenously express this gene can induce growth of cells in dense floating aggregates in reduced serum. Such findings indicate that hASH1 may be critical to the SCLC phenotype, including its characteristic aggregative behavior. The proposed series of studies now seek to determine: 1) features of lung cancer neuroendocrine differentiation and growth, particularly related to the function of paracrine growth factors, that may be modulated by hASH1; 2) the molecular events and changes in surface adhesion molecules that may underlie hASH1 mediated cell-cell adhesion in lung cancer; 3) the pathways regulating hASH1 gene expression in lung cancer, with an emphasis on evolutionary conserved factors from Drosophila neurogenesis; 4) the role of hASH1 expression in pulmonary endocrine cells in normal lung development and in response to experimental lung injury. These studies will provide a powerful approach to understanding the origins of SCLC and the differentiation relationships that link this tumor to the other major forms of this disease, potentially leading to the discovery of novel therapeutic targets in lung cancer.