Molecular Analysis of thyroid Cell Apoptosis and Carcinogenesis

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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.