Remediating Ing4 tumor suppressor deficiency using a zebrafish model

使用斑马鱼模型修复 Ing4 肿瘤抑制因子缺陷

• 批准号: 9794387
• 负责人: Katie L Kathrein
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9794387
• 关键词: Affect; Agar; Astrocytoma; Biological Assay; Cell physiology; Characteristics; Chromatin Remodeling Factor; Colorectal Cancer; Developmental Cell Biology; Disease; Disease Progression; Drug resistance; Embryo; Gene Expression; Genes; Genetic; Genetic Screening; Genetic Transcription; Goals; Grant; Growth; Hematologic Neoplasms; Hematopoietic Stem Cell Specification; Hematopoietic stem cells; Human; In Vitro; Libraries; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Mammalian Cell; Modeling; Molecular; Nature; Oncogenes; PHD Finger; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Play; Primary carcinoma of the liver cells; Proteins; Publications; Regulation; Role; Signal Transduction Pathway; Solid Neoplasm; Stem cells; Testing; Therapeutic; Tissues; Tumor Cell Line; Tumor Suppressor Proteins; Zebrafish; base; cancer cell; carcinogenesis; career; combat; genetic inhibitor; inhibitor/antagonist; loss of function; malignant breast neoplasm; neoplastic cell; outcome forecast; screening; small molecule; small molecule inhibitor; stem-like cell; success; targeted treatment; therapy resistant; trait; transcriptome sequencing; transcriptomics; tumor; tumor progression

ABSTRACT The multifaceted nature of cancer results in a disease that is complicated and difficult to treat. One common characteristic of this disease is the ability of cancer cells to re-acquire stem-cell like traits resulting in aberrant gene expression and resistance to therapy. As the molecular networks that are frequently aberrant in cancer are also utilized by normal stem cells, it is critical to understand how these pathways and mechanisms function in stem cells and are harnessed by cancer cells to promote disease progression. Aberrant gene expression in tumors is often a result of oncogene expression or tumor suppressor inactivation. Tumor suppressors are particularly challenging to target as these proteins are often missing or present only at very low levels in tumor cells. Our lab has recently identified the tumor suppressor, ING4, a chromatin modifier and a transcriptional regulator containing a PHD finger domain, as a critical regulator of hematopoietic stem cell specification. ING4 has been shown to be inactivated in several types of human cancer, including breast, prostate, colorectal, ovarian and lung cancers, astrocytomas, and hepatocellular carcinomas. Loss of ING4 expression is associated with a poor prognosis but the mechanisms of tumor-suppressive functions of ING4 are not yet fully understood. A potential mechanism of tumor suppressor activity of ING4 is through its negative regulation of the NF-B pathway, implicated in carcinogenesis, tumor progression and drug resistance. We found that Ing4 depletion in zebrafish stimulates NF-B activity and NF-B inhibition can rescue HSC deficiency caused by the loss of Ing4. Our proposed Specific Aims will use both genetic and pharmacological approaches, both in developing zebrafish and in ING4-deficient human tumor cells, to identify potential mechanisms for combating the loss of this protein in cancer. Aim 1 is to investigate the effects of Ing4 inactivation in zebrafish on gene expression and to determine if targeting of gene expression pathways that are upregulated upon loss of Ing4 would rescue the effects of Ing4 inactivation on HSC specification in zebrafish. Aim 2 is to determine if small molecule inhibitors of the NF-κB and other upregulated pathways would rescue the effects of Ing4 loss of function in zebrafish. Aim 3 is to identify genes and pathways, inhibition of which remediates cellular effects of ING4 inactivation in mammalian tumor cells, by using the results of the analysis in zebrafish and of a genetic screen conducted in ING4-deficient human tumor cells. The success of the proposed study will serve as the basis for identifying drugs that could remediate phenotypic effects of the ING4 deficiency, with the ultimate goal of developing therapeutic strategies for cancers where ING4 has been inactivated.

抽象的 癌症的多面性导致了一种复杂且难以治疗的疾病。 这种疾病的特征是癌细胞重新获得干细胞样特征的能力，从而导致异常 作为癌症中经常出现异常的分子网络。 也被正常干细胞利用，了解这些途径和机制如何发挥作用至关重要 存在于干细胞中，并被癌细胞利用以促进疾病进展。 肿瘤通常是癌基因表达或抑癌基因失活的结果。 靶向特别具有挑战性，因为这些蛋白质在肿瘤中经常缺失或仅以非常低的水平存在 我们的实验室最近发现了肿瘤抑制因子 ING4、染色质修饰剂和转录因子。 含有 PHD Finger 结构域的调节因子，作为造血干细胞规范的关键调节因子。 已被证明在多种人类癌症中失活，包括乳腺癌、前列腺癌、结直肠癌、 卵巢癌、肺癌、星形细胞瘤和肝细胞癌 ING4 表达缺失。 与不良预后相关，但 ING4 的肿瘤抑制功能机制尚未完全阐明 ING4 的肿瘤抑制活性的一个潜在机制是通过其负调节。 我们发现 Ing4 与致癌、肿瘤进展和耐药性有关。 斑马鱼的耗竭会刺激 NF-κB 活性，抑制 NF-κB 可以挽救由 NF-κB 引起的 HSC 缺乏。 我们提出的具体目标将同时使用遗传和药理学方法。 开发斑马鱼和 ING4 缺陷的人类肿瘤细胞，以确定对抗的潜在机制 目标 1 是研究斑马鱼中 Ing4 失活对基因的影响。 表达并确定是否靶向因 Ing4 丢失而上调的基因表达途径 目的 2 是确定 Ing4 失活对斑马鱼 HSC 规范的影响是否小。 NF-κB 和其他上调途径的分子抑制剂将挽救 Ing4 缺失的影响 目标 3 是确定斑马鱼的基因和通路，抑制这些基因和通路可以修复细胞效应。 通过使用斑马鱼和遗传基因的分析结果，哺乳动物肿瘤细胞中的 ING4 失活 在 ING4 缺陷的人类肿瘤细胞中进行的筛选将作为拟议研究的成功。 确定药物可以修复 ING4 缺陷的表型效应的基础，最终目标 开发针对 ING4 已失活的癌症的治疗策略。