Understanding the Roles of REGgamma in Anaplastic Thyroid Cancer Progression

了解 REGgamma 在甲状腺未分化癌进展中的作用

基本信息

批准号：
8127759
负责人：
XIAOTAO LI
金额：
$ 22.67万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-03 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8127759
关键词：
Address Antineoplastic Agents Biological Biological Carcinogenesis Cancer Control Cancer cell line Cell Cycle Cell Cycle Regulation Colorectal Cancer Development Event Family Health Human Ki antigen Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of thyroid Mediating Medicine Mitogen-Activated Protein Kinase Kinases Mitotic Cell Cycle Molecular Oncogenic Papillary thyroid carcinoma Phosphorylation Phosphotransferases Play Post-Translational Protein Processing Property Proteasome Inhibitor Proteins Regulation Role Sampling Series Signal Transduction Testing Therapeutic Thyroid carcinoma Tissue Array Analysis Tissue Microarray anaplastic thyroid cancer base cancer cell carcinogenesis clinical application insight multicatalytic endopeptidase complex novel novel therapeutics overexpression protein degradation tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Understanding the Roles of REG? in Anaplastic Thyroid Cancer Progression (Summary) Anaplastic thyroid cancer (ATC) is the most advanced and aggressive thyroid cancer and is the least likely to respond to treatment. Genetically, alteration of p53, p21Waf/Cip1 as well as other cell cycle regulators may be responsible for the transformation of well-differentiated thyroid cancer cells to ATC. In addition, oncogenic conversion of B-RAF occurs in ~44% of papillary thyroid carcinomas and 24% of anaplastic thyroid carcinomas. However, the carcinogenesis of ATC is still poorly understood and novel, efficient, therapeutic approaches have yet to be developed. We have provided evidence that p21 is a direct target of REG?-proteasome and that REG? is involved in promoting cell growth and cell cycle regulation. Furthermore, we found a series of other cell cycle regulators are also targets of REG?-proteasome. Preliminary studies indicate an abnormally high expression of REG?, non-detectable p21 level in anaplastic thyroid cancer samples, and potential regulation of REG? activity by B-RAF/MAP3K mediated phosphorylation. In this proposal, we hypothesize that a high level of REG? and depletion/reduction of p21 along with other cell cycle regulators may be responsible for ATC progression and that the regulation of REG? by B-RAF/MAP3K signaling may be a novel mechanism in ATC carcinogenesis. To test our hypothesis, we propose to further characterize protein levels of REG?, p21, p53, and the other cell cycle regulators targeted by REG? in ATC tissue array. We also propose to examine the impact of REG? and its target protein on carcinogenesis and biological properties in thyroid cancer cell lines. Finally, we will investigate the molecular details of phosphorylation of REG? by B-RAF/MAP3K kinases in ATC progression. Considering the roles of B-RAF in malignant thyroid cancer and colorectal cancer and "coincidental" involvement of REG? in these cancers, this proposal seeks to pioneer a novel study that may address some fundamental questions in malignant cancer progression and may provide further insight into the clinical application of cancer control. PUBLIC HEALTH RELEVANCE: The proteasome activator, REG?, has been known to express highly in two malignant cancers, thyroid cancer and colorectal cancer, and may play an important role in the progression of these cancers. This project is to understand the tumorigenic role of REG? in anaplastic thyroid cancer, the most malignant thyroid cancer, and results from this study will be of direct relevance to medicine. Considering proteasome inhibitor has emerged as a truly intriguing anticancer agent, this project may provide the basis for the development of novel therapeutics for human cancers.

描述（由申请人提供）：了解REG的作用吗？在塑性甲状腺癌的进展（摘要）中，甲状腺癌（ATC）是最先进和侵略性的甲状腺癌，并且最不可能对治疗做出反应。从遗传上讲，p53，p21WAF/CIP1以及其他细胞周期调节剂的改变可能是导致良好差异化的甲状腺癌细胞转化为ATC的。另外，B-RAF的致癌转化率发生在约44％的甲状腺甲状腺癌和24％的甲状腺甲状腺癌中。然而，ATC的致癌作用仍然鲜为人知，新颖，高效，治疗方法尚未开发。我们提供了证据表明p21是reg的直接目标？参与促进细胞生长和细胞周期调节。此外，我们发现一系列其他细胞周期调节剂也是Reg的靶标？初步研究表明，在甲状腺甲状腺癌样本中，REG的异常表达异常高，不可检测的P21水平以及REG的潜在调节？ B-RAF/MAP3K介导的磷酸化活性。在此提案中，我们假设高水平的REG？ p21以及其他细胞周期调节剂的耗竭/减少可能负责ATC进展以及REG的调节？ B-RAF/MAP3K信号传导可能是ATC癌变中的一种新机制。为了检验我们的假设，我们建议进一步表征REG的蛋白质水平，P21，P53和REG靶向的其他细胞周期调节剂？在ATC组织阵列中。我们还建议检查REG的影响吗？及其在甲状腺癌细胞系中癌变和生物学特性的靶蛋白。最后，我们将研究REG磷酸化的分子细节？由B-RAF/MAP3K激酶在ATC进程中。考虑到B-RAF在恶性甲状腺癌和大肠癌中的作用以及REG的“偶然”参与？在这些癌症中，该提案旨在拓展一项新的研究，该研究可能解决恶性癌症进展的一些基本问题，并可能会进一步了解癌症控制的临床应用。公共卫生相关性：已知蛋白酶体激活剂在两种恶性肿瘤，甲状腺癌和大肠癌中表达高度表达，并且可能在这些癌症的进展中起重要作用。这个项目是为了了解REG的致瘤作用吗？在塑性甲状腺癌中，最恶性甲状腺癌，这项研究的结果将与医学直接相关。考虑到蛋白酶体抑制剂已成为一种真正有趣的抗癌剂，该项目可能为人类癌症的新疗法开发提供基础。