Upregulation of Nanog as an Innovative Mechanism for Cancer Drug Resistance.

Nanog 的上调作为癌症耐药性的创新机制。

• 批准号: 8827727
• 负责人: TZYY-CHOOU WU
• 金额: $ 17.62万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827727
• 关键词: Antineoplastic Agents; Apoptosis; Cancer Biology; Cancer Intervention; Cancer Model; Cancer Patient; Cancer Relapse; Cells; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical; Development; Disease; Disease Management; Drug resistance; Ectopic Expression; Event; Evolution; Face; Generations; Genes; Genetic Transcription; Health; Homeobox; Human; Immune; Immunologic Surveillance; Knowledge; Lead; Light; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Measures; Mediating; Modeling; Molecular; Mus; Ovarian; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pluripotent Stem Cells; Primary Neoplasm; Process; Public Health; Recurrence; Recurrent disease; Reporting; Resistance; Role; SCID Mice; SKOV3 cells; Signal Transduction; Small Interfering RNA; Staining method; Stains; Stem cells; Transcriptional Activation; Tumor Tissue; Up-Regulation; base; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; driving force; improved; innovation; insight; mortality; nanoparticle; neoplastic cell; novel; novel strategies; outcome forecast; pressure; programs; response; self-renewal; stem; stemness; success; therapy resistant; transcription factor; tumor; tumor progression

DESCRIPTION (provided by applicant): Cancer progression and dissemination is due to adaptation of tumor cells to internal immune defenses and to external therapy. Thus, to reduce the public health burden due to cancer, it is necessary to understand the molecular basis of this process of adaptation. We recently found that in the course of both immune and drug selection, tumor cells undergo evolution towards gain of Nanog, a homeobox transcription factor pivotal for the self-renewal of pluripotent stem cells. We reported that Nanog expression in tumor tissue correlates with clinical prognosis. Furthermore, we found that Nanog converts tumor cells into a stem-like state and enables them to escape immune control through the Tcl1a-Akt pathway. Since the stem-like state permits indefinite self-renewal of cells, and since the Akt pathway coordinates the activation of a host of pro-survival signals, we reason that Nanog also confers drug resistance to tumor cells. We hypothesize that gain of Nanog underlies adaptation of tumor cells to host immune defenses as well as to therapy, and thus may represent a major driving force for cancer progression. As we have already established the role of Nanog in immune escape, the purpose of the current project is to investigate the role of Nanog in drug resistance. Our specific aims are to: (1) characterize the evolution of tumor cells towards Nanog expression and gain of a stem-like phenotype under drug selection by chemotherapy; (2) characterize the role of Nanog in conferring drug resistance to tumor cells; and (3) characterize the molecular mechanisms through which Nanog mediates drug resistance in tumor cells. The successful implementation of this project will be significant for several reasons. First, it reveals Nanog as molecular link between the stem-like state and drug resistance in tumor cells. This insight would directly lead to more successful choice of therapy and management of disease in cancer patients. Second, by identifying the Nanog-Tcl1a-Akt pathway as a gateway to both immune escape and drug resistance, this study sheds light on the process of cancer adaptation. Third, this project introduces a new approach to cancer chemotherapy. In particular, this study will prove the principle that the transcription network of stem cells can be rationally targeted to overcome the problem of cancer drug resistance. Based on these reasons, we believe this study will greatly advance our knowledge of cancer biology and have strong public health impact.

描述（由申请人提供）：癌症的进展和传播是由于肿瘤细胞对内部免疫防御和外部治疗的适应。因此，为了减轻由于癌症的公共卫生负担，有必要了解这种适应过程的分子基础。我们最近发现，在免疫选择和药物选择过程中，肿瘤细胞经历了Nanog增益的进化，Nanog是多能干细胞自我更新的同源曲托转录因子关键。我们报道了肿瘤组织中的Nanog表达与临床预后相关。此外，我们发现Nanog将肿瘤细胞转化为茎状状态，并使它们能够通过TCL1A-AKT途径逃脱免疫控制。由于茎状状态允许无限期的细胞自我更新，并且AKT途径协调了许多促生物寿命的宿主的激活，因此我们认为nanog还赋予了对肿瘤细胞的耐药性。我们假设纳米的增益是肿瘤细胞适应免疫防御和治疗的基础，因此可能代表了癌症进展的主要驱动力。由于我们已经确定了Nanog在免疫逃生中的作用，因此当前项目的目的是研究Nanog在耐药性中的作用。我们的具体目的是：（1）表征肿瘤细胞向Nanog表达的演变，并通过化学疗法选择药物选择的茎样表型； （2）表征纳米在赋予对肿瘤细胞耐药性的作用； （3）表征纳米纳米介导肿瘤细胞耐药性的分子机制。由于几个原因，该项目的成功实施将是重要的。首先，它揭示了Nanog是肿瘤细胞中干状状态与耐药性之间的分子联系。这种见解将直接导致更成功地选择癌症患者的疾病治疗和管理。其次，通过将Nanog-TCL1A-AKT途径鉴定为通往免疫逃逸和耐药性的门户，这项研究阐明了癌症适应过程。第三，该项目引入了一种新的癌症化疗方法。特别是，这项研究将证明可以将干细胞的转录网络合理地靶向以克服癌症耐药性问题。基于这些原因，我们认为这项研究将大大提高我们对癌症生物学的了解，并具有强烈​​的公共卫生影响。