Molecular Mechanism of cIAP1 in Malignant Progression of Human Cancer

cIAP1在人类癌症恶性进展中的分子机制

• 批准号: 14570454
• 负责人: IMOTO Issei
• 金额: $ 2.3万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570454/
• 关键词: Apoptosis; cIAP1; Esophageal Cancer; Cervical Cancer

Recently we reported that cIAP1, an inhibitor of apoptosis, is overexpressed through 11q22 amplification in cell lines derived from esophageal squamous cell carcinomas and is associated with resistance of esophageal squamous cell carcinomas to drug-induced apoptosis.(1) Because amplification of 11q22 has been implicated in other malignancies also, including cervical squamous cell carcinomas (CSCCs), we attempted to correlate amplification and overexpression of cIAP1 with radiation sensitivity in CSCC-derived cell lines and primary CSCC tumors. CSCC cell lines with amplification and consistent overexpression of cIAP1 showed significant resistance to radiation-induced cell death as compared with lines without cIAP1 amplification. Immunohistochemical analysis of 70 primary CSCCs from patients treated only with radiotherapy demonstrated that both overall survival and local recurrence-free survival was significantly poorer among patients with tumors showing high levels of nuclear cIAP1 staining than among patients whose tumors revealed little or no nuclear cIAP1. Multivanate analysis showed nuclear cIAP1 staining to be an independent predictive factor for local recurrence-free survival after radiotherapy among patients with CSCC.(2) In order to identify molecules, which interact with cIAP1, we performed bacterial and yeast two-hybrid screening. Although we identified one mitochondrial protein as candidate, we failed to validate the interaction between those two molecules in vivo. We will try to identify other molecules using immunopreapitation and TOF-MS system. We are also analyzing the effect of down-regulation of cIAP1 on spontaneous and drug-induced apoptosis in cells with overexpression of this protein using siRNA technique

最近我们报道了细胞凋亡抑制剂 cIAP1 通过 11q22 扩增在食管鳞状细胞癌衍生的细胞系中过表达，并且与食管鳞状细胞癌对药物诱导的细胞凋亡的抵抗相关。（1）因为 11q22 的扩增已被证实cIAP1 也与其他恶性肿瘤有关，包括宫颈鳞状细胞癌 (CSCC)，因此我们尝试将 cIAP1 的扩增和过度表达关联起来对 CSCC 衍生细胞系和原发性 CSCC 肿瘤具有辐射敏感性。与没有 cIAP1 扩增的细胞系相比，cIAP1 扩增和一致过表达的 CSCC 细胞系对辐射诱导的细胞死亡具有显着的抵抗力。对仅接受放射治疗的患者的 70 个原发性 CSCC 进行的免疫组织化学分析表明，与肿瘤细胞核 cIAP1 染色很少或没有的患者相比，细胞核 cIAP1 染色水平较高的肿瘤患者的总生存期和局部无复发生存期均显着较差。 Multivanate分析显示核cIAP1染色是CSCC患者放疗后局部无复发生存的独立预测因素。(2)为了鉴定与cIAP1相互作用的分子，我们进行了细菌和酵母双杂交筛选。尽管我们确定了一种线粒体蛋白作为候选蛋白，但我们未能在体内验证这两种分子之间的相互作用。我们将尝试使用免疫沉淀和 TOF-MS 系统来鉴定其他分子。我们还使用 siRNA 技术分析了 cIAP1 下调对该蛋白过度表达的细胞自发性和药物诱导的细胞凋亡的影响

项目成果

Imoto I, Inazawa J, et al.: "Expression of cIAP1, a target for 11q22 amplification, correlates with resistance of cervical cancers to radiotherapy"Cancer Research. 62・17. 4860-4866 (2002)

Imoto I、Inazawa J 等人：“11q22 扩增靶标 cIAP1 的表达与宫颈癌对放射治疗的抵抗力相关”Cancer Research 62・17 (2002)。

Saito-Ohara F, Imoto I, Inazawa J, et al.: "The Xq22 inversion breakpoint interrupted a novel Ras-like GTPase gene in a patient with Duchenne muscular dystrophy and profound mental retardation"American Journal of Human Genetics. 71・3. 637-645 (2002)

Saito-Ohara F、Imoto I、Inazawa J 等人：“Xq22 倒位断点中断了杜氏肌营养不良症和严重智力低下患者的新型 Ras 样 GTPase 基因”《美国人类遗传学杂志》71·3。 637-645 (2002)

Hirasawa A, Inazawa J, Imoto I, et al.: "Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets"Clinical Cancer Research. (印刷中). (2003)

Hirasawa A、Inazawa J、Imoto I 等人：“卵巢透明细胞腺癌中 17q21-q24 增益与不良预后的关联以及 PPM1D 和 APPBP2 作为可能的扩增靶点的识别”（出版中）。 ）

Imoto I, Inazawa J, et al.: "Identification of ZASC1 encoding a Kruppel-like zinc finger protein as a novel target for 3q26 amplification in esophageal squamous-cell carcinomas."Cancer Research. 63. 5691-5696 (2003)

Imoto I、Inazawa J 等人：“鉴定编码 Kruppel 样锌指蛋白的 ZASC1 作为食管鳞状细胞癌 3q26 扩增的新靶标。”癌症研究。

Hirasawa A, Imoto I, Inazawa J, et al.: "Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets."Clinical Cancer Research. 9. 1995-2004 (2003)

Hirasawa A、Imoto I、Inazawa J 等人：“卵巢透明细胞腺癌中 17q21-q24 增益与预后不良的关联，以及将 PPM1D 和 APPBP2 识别为可能的扩增靶标。”临床癌症研究。