Epithelial-mesenchymal transition regulators in radioresistance and DNA repair

放射抗性和 DNA 修复中的上皮-间质转化调节因子

基本信息

批准号：
8751065
负责人：
Li Ma
金额：
$ 33.2万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8751065
关键词：
ATM Signaling Pathway Affect Applications Grants Ataxia-Telangiectasia-Mutated protein kinase Behavior Biological Markers Breast Cancer Cell CHEK2 gene CHES1 gene Cancer Center Cancer cell line Cause of Death Cell Cycle Checkpoint Cell Cycle Progression Cells Characteristics Clinical Collaborations DNA DNA Damage DNA Repair DNA damage checkpoint DNA lesion Data Deubiquitination Development Diagnostic Down-Regulation E-Cadherin Epithelial Exhibits Feedback Future Health Human In Vitro Ionizing radiation Knowledge LIFR gene Malignant Neoplasms Malignant neoplasm of lung Mastectomy Mediating Mesenchymal Messenger RNA MicroRNAs Molecular Neoplasm Metastasis Operative Surgical Procedures Outcome Pathway interactions Patients Phosphorylation Phosphorylation Site Phosphotransferases Play Pre-Clinical Model Process Property Protein Kinase Proteins Radiation Radiation Induced DNA Damage Radiation Oncology Radiation Physics Radiation Tolerance Radiation therapy Radiation-Sensitizing Agents Radioresistance Recurrence Regulation Reporting Research Resistance Role Serine Therapeutic Therapeutic Intervention Therapeutic Uses Toxic effect Up-Regulation Woman Work base cancer stem cell chemotherapy high risk homologous recombination improved in vivo inhibitor/antagonist insight interest malignant breast neoplasm neoplastic cell novel public health relevance research study response stem therapeutic target transcription factor tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Radiation therapy, the therapeutic use of ionizing radiation to induce damage to the DNA, plays an important role in cancer management. DNA lesions are recognized by cell cycle checkpoints, leading to activation of DNA damage repair pathways. Recently, cancer stem cells have been shown to promote tumor radioresistance through activation of DNA damage response. In addition, a trans-differentiation process, termed epithelial-mesenchymal transition (EMT), is thought to promote metastasis and generate stem-like cells. Besides its implication in tumor progression and metastasis, EMT has been shown to be associated with characteristics of cancer stem cells, including chemoresistance and radioresistance. However, it is not clear which EMT regulators play causal roles in these properties. We and others have previously uncovered microRNA-mediated regulation of metastasis and EMT. Moreover, we provided proof-of-principle evidence that therapeutic silencing of a pro-metastatic microRNA can block metastasis in a preclinical model. In this research, we intend to seek EMT-regulating transcription factors and microRNAs that represent novel regulators of radioresistance and DNA damage repair, determine their mechanism of action and regulation of expression, and explore their potential use as new cancer biomarkers and therapeutic targets. In preliminary studies, we found that two recently reported EMT regulators, ZEB1 and miR-205, negatively regulate each other and play opposing roles in modulating radiosensitivity of tumor cells. Furthermore, our data point to a role of ATM signaling in stabilizing ZEB1 and a role of ZEB1 in promoting deubiquitination-mediated stabilization of CHK1, a protein kinase that is required for cell cycle checkpoint control and homologous recombination-mediated DNA damage repair. In proposed future studies, we will: 1) investigate the role of ZEB1 and miR-205 in tumor radioresistance and cancer stem cell properties; 2) identify the mechanism by which ZEB1 regulates radiosensitivity and DNA damage response; 3) determine how ZEB1 is upregulated in response to radiation and DNA damage; 4) study the involvement of ZEB1 and miR-205 in human tumors and the therapeutic potential. The knowledge gained from these studies will provide new insights into how specific EMT regulators contribute to tumor radioresistance and DNA damage repair and may have significant clinical implications.

描述（由申请人提供）：放射疗法是电离辐射诱导DNA损害的治疗用途，在癌症管理中起着重要作用。 DNA病变通过细胞周期检查点识别，导致DNA损伤修复途径的激活。最近，癌症干细胞已被证明可以通过激活DNA损伤反应来促进肿瘤放射线。此外，被认为是上皮 - 间质转变（EMT）的反差异过程被认为可以促进转移并产生样干细胞。除了其对肿瘤进展和转移的影响外，EMT还显示与癌症干细胞的特征有关，包括化学耐药性和放射性。但是，尚不清楚哪些EMT调节器在这些属性中扮演因果角色。我们和其他人以前已经发现了MicroRNA介导的转移和EMT调节。此外，我们提供了原理证据证明，促旋晶的治疗沉默可以阻止临床前模型中的转移。在这项研究中，我们打算寻求代表辐射抗性和DNA损伤修复的新调节剂的EMT调节因子和microRNA，确定其作用机理和表达机制，并探索其作为新的癌症生物标志物和治疗靶标的潜在用途。在初步研究中，我们发现两名最近报道了EMT调节剂Zeb1和miR-205，对彼此进行负调控，并在调节肿瘤细胞的放射辐射效率方面起着相反的作用。此外，我们的数据表明ATM信号在稳定Zeb1中的作用以及Zeb1在促进去泛素化介导的CHK1稳定稳定中的作用，CHK1是一种蛋白激酶，这是细胞周期控制和同源重组介导的DNA损害修复所必需的蛋白激酶。在拟议的未来研究中，我们将：1）研究Zeb1和miR-205在肿瘤放射性和癌症干细胞特性中的作用； 2）确定Zeb1调节放射性敏感性和DNA损伤反应的机制； 3）确定Zeb1如何响应辐射和DNA损伤； 4）研究Zeb1和miR-205在人类肿瘤中的参与和治疗潜力。从这些研究中获得的知识将提供新的见解，以了解特定的EMT调节剂如何有助于肿瘤放射线和DNA损伤修复，并可能具有显着的临床意义。