Gene expression profiles of thymic neuroendocrine tumors (carcinoids) with ectopic ACTH syndrome. Homo sapiens

Although there has been increased knowledge about the molecular biology of neuroendocrine tumors (NETs), little is known about thymic carcinoids and even less about those with excessive hormone disorders, such as ectopic ACTH syndrome. This study was designed to gain insights into molecular networks underlying the tumorigenesis of thymic carcinoids with ACTH secretion. By an approach integrating cDNA microarray and methods of computational biology, we compare gene expression profile between ACTH-producing thymic carcinoids and normal thymus. Totally there are 63 biological categories increased and 108 decreased in thymic carcinoids. Cell proliferation was stimulated which may explain the relatively uncontrolled cell growth of the tumor. Dysregulation of Notch signaling pathway was likely underlying the neuroendocrine features of this type of tumors. Moreover, the inhibition of the immunity and the increased neuropeptide signaling molecules, POMC and its sorting molecule CPE, made the clinical manifestation reasonable and thus validated the array data. In conclusion, thymic carcinoids have distinguished gene expression pattern from the normal thymus and they are characterized by deregulations of a series of biofunctions, which may be involved in the development of neuroendocrine tumor. This study hence has provided not only a detailed comprehension of the molecular pathogenesis of thymic carcinoid with ectopic ACTH syndrome, but also a road map to approach thymic neuroendocrine tumors at the system level. Overall design: Transcriptome profilings were performed to identify differentially expressed cDNAs between five samples (NCs) from thymic tumor-suffering patients with ectopic ACTH syndrome (i.e., NC1, NC2, NC3, NC4, NC5, NC6) and six samples (ACs) of the noncancerous thymuses (i.e., AC1, AC2, AC3, AC4, AC5).

尽管目前对神经内分泌肿瘤（neuroendocrine tumors, NETs）的分子生物学机制已有较为深入的认知，但针对胸腺类癌的研究仍相对匮乏，而对于伴发过量激素分泌紊乱（如异位促肾上腺皮质激素综合征）的胸腺类癌，相关研究则更为稀缺。本研究旨在解析伴促肾上腺皮质激素（ACTH）分泌的胸腺类癌发生发展背后的分子调控网络。本研究整合cDNA微阵列技术与计算生物学方法，对比分析了分泌ACTH的胸腺类癌与正常胸腺组织的基因表达谱差异。结果显示，胸腺类癌组织中共计63个生物学功能类别呈现表达上调，108个类别呈现表达下调。肿瘤细胞增殖通路被激活，这或可解释该肿瘤相对失控的细胞生长特性。Notch信号通路的失调可能是此类肿瘤呈现神经内分泌表型的分子基础。此外，免疫抑制状态以及神经肽信号分子——阿黑皮素原（POMC）及其分选分子羧肽酶E（CPE）——的表达上调，与该类肿瘤的临床表型相符，由此验证了芯片检测结果的可靠性。综上，胸腺类癌与正常胸腺组织的基因表达模式存在显著差异，其特征为一系列生物学功能的失调，而这些失调或参与神经内分泌肿瘤的发生发展过程。因此，本研究不仅深入阐明了伴异位ACTH综合征的胸腺类癌的分子发病机制，同时也为从系统层面解析胸腺神经内分泌肿瘤提供了研究框架。实验设计概况：本研究通过转录组谱分析，对比了5例样本（NC组，即NC1、NC2、NC3、NC4、NC5、NC6，来自伴异位ACTH综合征的胸腺类癌患者）与6例非癌性胸腺组织样本（AC组，即AC1、AC2、AC3、AC4、AC5）之间的差异表达cDNA。