Anti-metastatic Effect of MCIP1 in Thyroid Cancer

MCIP1在甲状腺癌中的抗转移作用

• 批准号: 6851247
• 负责人: Matthew D Ringel
• 金额: $ 12.86万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6851247
• 关键词: FK506; calcineurin; cell line; cell migration; cell motility; cell surface receptors; cyclosporines; disease /disorder model; drug screening /evaluation; enzyme activity; enzyme inhibitors; gene expression; laboratory mouse; metastasis; microarray technology; mitogen activated protein kinase; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neuropeptides; phospholipase C; polymerase chain reaction; protein kinase C; thyroid neoplasm; tumor suppressor proteins; xenotransplantation

DESCRIPTION (provided by applicant): Thyroid cancer is the most common endocrine malignancy and its incidence is the second fasting rising of all cancers in the United States. Therapy for localized thyroid cancer is effective, but patients with distant metastasis or locally aggressive tumors have a poor prognosis. Despite major advances in defining the pathogenic mechanisms for thyroid cancer development, the pathways responsible for thyroid cancer progression remain poorly defined. Thus, characterizing pathways that inhibit thyroid cancer invasion and metastasis represents an important goal for developing targeted therapies for this disease. GPR54 has been characterized to be the receptor for an endogenously produced metastasis inhibiting peptide, metastin (KiSS-1 gene product). In overexpression models, GPR54 is a G-alpha q-11-coupled receptor that activates phospholipase C and other pathways, resulting in metastasis inhibition. More recently, patients with inactivating mutations in the GPR54 gene and GPR54 null mice have been shown to develop hypogonadotropic hypogonadism through uncertain mechanisms. In thyroid cancer, we have demonstrated that GPR54 is overexpressed in papillary thyroid cancer, but is lost in follicular thyroid cancer, the subtype with the greatest predilection for distant metastasis. We have shown that, in addition to PLC activation, the endogenously expressed GPR54 aIso activates E RKI/2, but not p38 MAPK in thyroid cancer cells. Because PLC, ERK and Akt activation induce cell proliferation and migration, we reasoned that GPR54 must also interact with other pathways to exert its inhibitory effect. To identify GPR54-altered genes that might be related to these properties, we performed cDNA array studies on total RNA isolated from GPR54-expressing thyroid cancer cells after 1 and 24 hours of metastin stimulation. In all experiments (duplicate RNA batches for each time point), and at both time points, the gene encoding MCIP1 (calcineurin inhibitor) was upregulated. These data have been confirmed by quantitative RT-PCR and functional studies have demonstrated that metastin down-regulates calcineurin activity in thyroid cancer cells. The purpose of this grant application is to determine if inhibition of calcineurin and upregulation of MCIP1 are involved in the anti-proliferative and migratory effects of metastin, and if they represent targets for therapy of this aggressive and frequently fatal disease.

描述（由申请人提供）：甲状腺癌是最常见的内分泌恶性肿瘤，其发病率在美国所有癌症中排名第二。局部甲状腺癌的治疗是有效的，但远处转移或局部侵袭性肿瘤的患者预后不良。尽管在定义甲状腺癌发展的致病机制方面取得了重大进展，但导致甲状腺癌进展的途径仍然定义不清。因此，表征抑制甲状腺癌侵袭和转移的途径代表了开发针对该疾病的靶向疗法的重要目标。GPR 54已被表征为内源性产生的转移抑制肽metastin（KiSS-1基因产物）的受体。在过表达模型中，GPR 54是一种G-α q-11偶联受体，可激活磷脂酶C和其他途径，导致转移抑制。最近，GPR 54基因失活突变的患者和GPR 54缺失小鼠已被证明通过不确定的机制发展为低促性腺激素性性腺功能减退症。在甲状腺癌中，我们已经证明GPR 54在乳头状甲状腺癌中过表达，但在滤泡状甲状腺癌中丢失，滤泡状甲状腺癌是最容易发生远处转移的亚型。我们已经证明，在甲状腺癌细胞中，除了PLC激活外，内源性表达的GPR 54也激活ERKI/2，但不激活p38 MAPK。由于PLC、ERK和Akt激活诱导细胞增殖和迁移，我们推断GPR 54还必须与其他途径相互作用以发挥其抑制作用。为了确定GPR 54改变的基因，可能与这些属性，我们进行了cDNA阵列研究总RNA分离GPR 54表达甲状腺癌细胞后1和24小时的metastin刺激。在所有实验中（每个时间点重复RNA批次），在两个时间点，编码MCIP 1（钙调磷酸酶抑制剂）的基因上调。这些数据已经通过定量RT-PCR和功能研究证实，metastin下调甲状腺癌细胞中的钙调神经磷酸酶活性。该授权申请的目的是确定钙调磷酸酶的抑制和MCIP 1的上调是否参与metastin的抗增殖和迁移作用，以及它们是否代表这种侵袭性和经常致命的疾病的治疗靶点。