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

• 批准号: 9095257
• 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
• 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/9095257
• 关键词: ATM Signaling Pathway; Affect; Applications Grants; Behavior; Biological Markers; Breast Cancer Cell; Breast Cancer cell line; CHEK1 gene; CHEK2 gene; Cancer Center; 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; Investigational Therapies; 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 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; ataxia telangiectasia mutated protein; base; cancer biomarkers; cancer stem cell; chemotherapy; high risk; homologous recombination; improved outcome; in vivo; inhibitor/antagonist; insight; interest; knock-down; malignant breast neoplasm; neoplastic cell; novel; radiation response; radioresistant; research study; response; stem; targeted treatment; therapeutic target; transcription factor; tumor; tumor progression

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）： 放射治疗，电离辐射诱导DNA损伤的治疗用途，在癌症管理中起着重要作用。DNA损伤被细胞周期检查点识别，导致DNA损伤修复途径的激活。近年来，研究发现肿瘤干细胞可通过激活DNA损伤反应而增强肿瘤的辐射抗性。此外，被称为上皮-间充质转化（EMT）的转分化过程被认为促进转移并产生干细胞样细胞。除了其在肿瘤进展和转移中的意义外，EMT已被证明与癌症干细胞的特性相关，包括化学抗性和放射抗性。然而，目前尚不清楚哪些EMT调节剂在这些属性中发挥因果作用。我们和其他人以前已经发现了microRNA介导的转移和EMT的调节。此外，我们提供了原则性证据，即促转移microRNA的治疗性沉默可以在临床前模型中阻断转移。在这项研究中，我们打算寻找EMT调节转录因子和microRNA，它们代表了辐射抗性和DNA损伤修复的新型调节因子，确定它们的作用机制和表达调节，并探索它们作为新的癌症生物标志物和治疗靶点的潜在用途。在初步研究中，我们发现两个最近报道的EMT调节因子，ZEB 1和miR-205，在调节肿瘤细胞的放射敏感性中相互负调控并发挥相反的作用。此外，我们的数据表明ATM信号在稳定ZEB 1中的作用，以及ZEB 1在促进去泛素化介导的CHK 1稳定中的作用，CHK 1是细胞周期检查点控制和同源重组介导的DNA损伤修复所需的蛋白激酶。在未来的研究中，我们将：1）研究ZEB 1和miR-205在肿瘤放射抗性和癌症干细胞特性中的作用; 2）确定ZEB 1调节放射敏感性和DNA损伤反应的机制; 3）确定ZEB 1如何在辐射和DNA损伤反应中上调; 4）研究ZEB 1和miR-205在人类肿瘤中的参与及其治疗潜力。从这些研究中获得的知识将为特定EMT调节剂如何促进肿瘤辐射抗性和DNA损伤修复提供新的见解，并可能具有重要的临床意义。