Molecular Analysis of thyroid Cell Apoptosis and Carcinogenesis

作为日本长崎医学研究的一项职责，必须根据原子弹幸存者积累的知识和经验，把重点放在与辐射有关的项目上。特别是自1991年以来，我们一直参与切尔诺贝利医疗援助计划，并为切尔诺贝利周围儿童甲状腺疾病的筛查和诊断做出了贡献。为了进一步扩展辐射诱导甲状腺组织发生的基础研究，特别是分子分析，我们重点研究了辐射从生理凋亡逃逸导致甲状腺细胞损伤的关键事件，并最终导致基因不稳定和细胞异常增殖。本实验设计比较了体外和体内甲状腺细胞分化和增殖受自分泌和旁分泌因子及TSH调控的情况。其中，TGFbeta是一种有效的生长抑制因子，我们研究了c-myc基因调控和5-c-myc-CAT抑制。PTHrP，甲状旁腺激素相关肽也是另一种参与甲状腺癌变的细胞因子，我们证实其在各类甲状腺癌组织中均有异常表达。我们进一步证实了PTHrP在多种内分泌肿瘤中的癌胎表达，并证实了反义PTHrP寡核苷酸的治疗作用。还分析了人甲状腺组织中TSH受体和ret癌基因的点突变。近年来，甲状腺特异性调控p53下游靶基因的研究陆续发表，证实了p53在甲状腺细胞凋亡和异常细胞增殖中的关键作用。结合在《甲状腺》、《国际癌症杂志》和《健康物理》上发表的临床数据，我们的实验室应用了差分显示和SAGE方法等基因搜索的新技术。进一步的研究计划在体外和体内实验系统阐明甲状腺肿瘤发生的分子机制。

As a duty of medical research in Nagasaki, Japan, it is essential to concentrate on the radiation-related projects based on the accumulated knowledge and experience of atomic bomb survivors. Especially we have been involved in the Chernobyl Medical Aid Program since 1991 and contributed to the screeming and diagnosis of childhood thyroid diseases around Chernobyl.To further extend the basic research, especially molecular analysis radiation-induced thyroid tuniorigenesis, we have focused on the critical events of thyroid cell damages induced by radiation escaping from physiological apoptosis, which can eventually induce gene instability and abnormal cell proliferation. The experimental design is compared of in vitro and in vivo thyroid cell differentiation and proliferation regulated by autocrine and paracrine factors in addition to TSH.Among them, TGFbeta is a potent growth-inhibiting cytokine which we demorrtrated the c-myc gene regulation and 5-c-myc-CAT suppression. PTHrP,parathyroid-hormone-related peptide is also another cytokine to be involved on thyroid carcinogenesis, which we confirmed the abnormal expression in various type of thyroid cancer tissues. We have further demonstrated the oncofetal expression of PTHrP in various endocrine tumors and the therapeutic rule of antisense PTHrP oligo nucleotide was confirmed. Point mutations of TSH receptor and ret oncogene are also analyzed in human thyroid tissues. Recently thyroid specific regulation of p53 down stream target genes has been published and a pivotal rule of p53 on thyroid apoptosis and abnormal cell proliferation is confirmed.Combined with the clinical data published in Thyroid, Int J.Cancer and Health Phys, the new technology of gene hunting such as differential display and SAGE methods is applied in our laboratory. Further studies are planned on clarification of molecular mechanism of thyroid tumorigenesis using in vitro and in vivo experimental systems.