Elucidation of thyroid carcinogenesis and clinical application of molecular targeting therapy

甲状腺癌发生机制的阐明及分子靶向治疗的临床应用

• 批准号: 19390253
• 负责人: YAMASHITA Shunichi
• 金额: $ 11.15万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2007
• 资助国家: 日本
• 起止时间: 2007 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-19390253/
• 关键词: 内分泌学; 甲状腺がん; 遺伝子多型解析; 細胞機能解析; 放射線影響; 分子標的治療; 病態生理; 放射線治療; 遺伝子多型; 細胞内情報伝達系; DNA損傷修復; 4.PMLボディー等の核内構造の形成機構の解析; がん基礎研究

In order to clarify the involvement of abnormalities of intracellular signaling pathway and genomic instability of thyroid carcinogenesis, we performed molecular analysis of related genes on thyroid cancers using operated thyroid tissues and cell culture systems. There were no specific abnormal genetic alterations on ARAF, RAPA1 and GNAQ on operated thyroid cancer tissues and cancer cell lines besides BRAF and RET?PTCs. The cell transformation assay suggested the involvement of ARAF abnormality in vitro, however, no ARAF mutation was proved in vivo. The data obtained suggested the relationship between DNA damage response and cell cycle regulation on thyroid cell transformation by irradiation. The molecular epidemiological study using Chernobyl samples suggested the involvement of FOXOE1 (TTF2) SNPs on genetic susceptibility on radiation-induced thyroid carcinogenesis although further confirmation is needed. Moreover, there were some disease-related SNPs of DNA damage response genes on thyroid carcinogenesis.In contrast clinical application of molecular targeting therapy has been hampered because of various barriers on clinical trial. The effectiveness of targeting restoration of p53 function has been proved but other molecules targeted are not yet applied yet. So we have tried the combination therapy of Gleevec and external radiation for the patients with advanced and anaplastic cancers with some partial response.

为了阐明细胞内信号通路异常和基因组不稳定性在甲状腺癌发生中的作用，我们利用手术切除的甲状腺组织和细胞培养系统对甲状腺癌的相关基因进行了分子分析。除BRAF和RET？PTCs外，手术切除的甲状腺癌组织和癌细胞系均未发现ARAF、RAPA1和GNAQ基因的特异性异常改变。体外细胞转化实验提示ARAF异常参与，而体内未发现ARAF突变。提示照射后甲状腺细胞转化过程中DNA损伤反应与细胞周期调控之间的关系。使用切尔诺贝利样本的分子流行病学研究表明，FOXOE1(TTF2)SNPs参与了辐射诱发甲状腺癌的遗传易感性，尽管还需要进一步证实。此外，在甲状腺癌的发生过程中还存在一些与疾病相关的DNA损伤反应基因SNPs，而分子靶向治疗由于临床试验中的各种障碍而阻碍了其临床应用。靶向修复P53功能的有效性已被证明，但其他靶向分子尚未得到应用。为此，我们尝试了格列卫联合外照射治疗部分有反应的晚期未分化癌患者。

项目成果

DHMEQ, a novel NF-kappaB inhibitor, suppresses growth, type I collagen accumulation in keloid fibroblasts.

DHMEQ 是一种新型 NF-kappaB 抑制剂，可抑制瘢痕疙瘩成纤维细胞的生长和 I 型胶原蛋白的积累。

• 发表时间: 2008
• 期刊: J Dermatol Sci 51(3)
• 作者: Makino S;Mitsutake N;Nakashima M;Saenko VA;Ohtsuru A;Umezawa K;Tanaka K;Hirano A;Yamashita S
• 通讯作者: Yamashita S

Differential effects of low, high doses of taxol in anaplastic thyroid cancer cells: possible implication of the pin 1 prolyl isomerase.

低、高剂量紫杉醇对未分化甲状腺癌细胞的不同作用：pin 1脯氨酰异构酶的可能影响。

• 发表时间: 2008
• 期刊: Exp Oncol 30(3)
• 作者: Pushkarev VM;Starenki DV;Saenko VA;Pushkarev VV;Kovzun OI;Tronko MD;Popadiuk ID;Yamashita S
• 通讯作者: Yamashita S

甲状腺ホルモン受容体遺伝子

甲状腺激素受体基因

• 发表时间: 2007
• 期刊: 【新版】甲状腺・副甲状腺超音波診断アトラス
• 作者: 比嘉由紀子;川田均;高村典子;大田黒嵩伸;Nguyen Thi Yen;Tran Hai Son;Nguyen Thuy Hoa;高木正洋;Eisei Noiri et al.;星野美保子・木股三善・西田憲正・清水雅浩;山下 俊一
• 通讯作者: 山下 俊一

Cancer screening with whole-body PET/CT for healthy asymptomatic people in Japan: re-evaluation of its test validity and radiation exposure.

• 发表时间: 2007
• 期刊: Asian Pacific journal of cancer prevention : APJCP
• 作者: N. Ghotbi;M. Iwanaga;A. Ohtsuru;Yoji Ogawa;S. Yamashita

A rapid non-radioactive technique for measurement of repair synthesis in primary human fibroblasts by incorporation of ethynyl deoxyuridine (EdU).

• DOI: 10.1093/nar/gkp023
• 发表时间: 2009-03
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Limsirichaikul S;Niimi A;Fawcett H;Lehmann A;Yamashita S;Ogi T
• 通讯作者: Ogi T