Role of Nucleostemin in Conferring The Drug Resistance of Hepatocellular Carcinoma

Nucleostemin 在赋予肝细胞癌耐药性中的作用

• 批准号: 9187447
• 负责人: ROBERT Y TSAI
• 金额: $ 7.43万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187447
• 关键词: Ablation; Address; Animal Model; BRCA1 gene; Biological Assay; Breast; Breast Cancer Cell; Cancer Etiology; Carcinoma; Cell Culture Techniques; Cell Death; Cells; Cisplatin; Clinical; DNA Damage; Data; Databases; Diethylnitrosamine; Double Strand Break Repair; Doxorubicin; Drug resistance; EXO1 gene; Event; Exhibits; Fluorouracil; Future; Genomic Instability; Genomics; Genotoxic Stress; Hep3B; Hepatocarcinogenesis; Heterogeneity; Home environment; Human; Hyperactive behavior; Knowledge; MDA MB 231; Malignant Bone Neoplasm; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Measures; Mediating; Mitotic; Mus; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Play; Primary carcinoma of the liver cells; Property; Proteins; RAD51C gene; RAD52 gene; Recruitment Activity; Research; Resistance; Role; Sampling; Site; Testing; The Cancer Genome Atlas; Tissue Microarray; base; bone; cancer cell; chemotherapeutic agent; clinically relevant; endodeoxyribonuclease SceI; genotoxicity; homologous recombination; improved; mRNA Expression; malignant breast neoplasm; mortality; neoplastic cell; overexpression; prevent; protein expression; public health relevance; recombinational repair; repaired; self-renewal; stem; targeted treatment; tumor

 DESCRIPTION (provided by applicant): Resistance of high-grade tumors to DNA damage-inducing chemotherapeutic agents (C/Ts) is a major cause of cancer mortality. Hepatocellular carcinoma (HCC) is well known for its innate resistance to C/Ts, but the underlying mechanisms remain unclear. Recent studies are beginning to home in on the notion that the progression and drug resistance of late-stage breast and ovarian cancers may depend on the homologous recombination (HR) repair pathway. My group studies a self-renewal mechanism controlled by a stem and cancer cell-enriched protein called nucleostemin (NS). We recently discovered a key activity of NS in promoting HR repair and protecting cancer cells from replication-induced DNA damage. We also found that NS is highly expressed in Hep3B (human HCC) cells and late-stage diethylnitrosamine (DEN)-induced mouse HCC. The objective of this R03 application is to obtain data to support the clinical relevance of NS in human HCC samples and its potential role in conferring HCC drug resistance via HR repair. We hypothesize that NS expression correlates with the malignancy of human HCC and that NS depletion will compromise the HR- based double-strand break (DSB) repair and chemoresistant property of HCC cells. This hypothesis is formulated based on the following reasons: 1) NS expression is significantly up-regulated in Hep3B cells and in DEN-induced HCC at the late carcinoma stage; 2) NS is required to maintain the continuous proliferation of Hep3B cells; 3) NS promotes HR-based repair and prevents genomic damage in breast (MDA-MB-231) and bone (U2OS) tumor cells; and 4) HR deficiency is known to sensitize breast, ovarian, prostate, and pancreatic cancers to C/Ts. To test our hypothesis, three specific aims will be pursued. Aim #1 will characterize the clinical relevance of NS in human HCC. Aim #2 will determine the effect of NS depletion on HR-based DSB repair in HCC cells. Aim #3 will determine the role of NS in mediating HCC drug resistance. As the outcome of this application, we will establish the clinical importance of NS by showing an increased or dysregulated NS expression in human HCC samples, define the relationship between NS expression and patients' clinical outcome, and provide functional evidence to support the role of NS in promoting the HR-based repair and chemoresistance in HCC cells, all of which are important preliminary data for our future R01 submission. If our hypothesis is proven true, it will impact on our knowledge of how HCC cells adapt to the hyperactive mitotic state and avoid fatal genomic instability at late stage, how HCC develop the innate property of chemoresistance, and whether HCC can be re-sensitized to C/Ts by NS ablation. Given the complexity of hepatocarcinogenesis and heterogeneity of HCC, combining C/Ts with a treatment that targets a common adaptive mechanism used by cancer cells offers an appealing strategy to improve the efficacy and tolerability of C/Ts.

 描述（由申请人提供）：高级别肿瘤对 DNA 损伤诱导化疗药物 (C/T) 的耐药性是癌症死亡的主要原因，众所周知，肝细胞癌 (HCC) 具有对 C/T 的先天耐药性。但其潜在机制仍不清楚。最近的研究开始关注晚期乳腺癌和卵巢癌的进展和耐药性可能取决于同源重组（HR）修复。我的团队研究了一种由干细胞和癌细胞富集的核蛋白 (NS) 控制的自我更新机制，我们最近发现了 NS 在促进 HR 修复和保护癌细胞免受复制诱导的 DNA 损伤方面的关键活性。发现 NS 在 Hep3B（人 HCC）细胞和晚期二乙基亚硝胺 (DEN) 诱导的小鼠 HCC 中高表达。此 R03 应用的目的是获得支持 NS 临床相关性的数据。人类 HCC 样本中的 NS 表达及其在通过 HR 修复赋予 HCC 耐药性中的潜在作用我们发现 NS 表达与人类 HCC 的恶性相关，并且 NS 耗竭将损害基于 HR 的双链断裂 (DSB) 修复和化疗特性。该假设是基于以下原因提出的：1）在晚期癌症阶段，Hep3B 细胞和 DEN 诱导的 HCC 中 NS 表达显着上调； Hep3B 细胞的持续增殖；3) NS 促进基于 HR 的修复并防止乳腺 (MDA-MB-231) 和骨 (U2OS) 肿瘤细胞的基因组损伤；4) HR 缺陷会使乳腺、卵巢、前列腺变得敏感。和胰腺癌与 C/T 的关系 为了检验我们的假设，我们将追求三个具体目标：描述其临床相关性。 人类 HCC 中的 NS 目标 #2 将确定 NS 耗竭对 HCC 细胞中基于 HR 的 DSB 修复的影响。目标 #3 将确定 NS 在介导 HCC 耐药性中的作用。通过显示人类 HCC 样本中 NS 表达增加或失调来了解 NS 的临床重要性，定义 NS 表达与患者临床结果之间的关系，并提供功能证据来支持 NS 在促进基于 HR 的修复和HCC 细胞的化疗耐药性，所有这些都是我们未来提交 R01 的重要初步数据，如果我们的假设被证明是正确的，它将影响我们对 HCC 细胞如何适应有丝分裂过度状态并避免晚期致命的基因组不稳定性的了解，鉴于肝癌发生的复杂性和 HCC 的异质性，HCC 如何发展化疗耐药的先天特性，以及 HCC 是否可以通过 NS 消融重新对 C/T 敏感。将 C/T 与针对癌细胞使用的常见适应性机制的治疗相结合，为提高 C/T 的疗效和耐受性提供了一种有吸引力的策略。

项目成果

Creating a graft-friendly environment for stem cells in diseased brains.

为患病大脑中的干细胞创造一个移植友好的环境。

• DOI: 10.1172/jci98490
• 发表时间: 2018-01-02
• 期刊: The Journal of clinical investigation
• 作者: R. Y. Tsai

Nucleostemin Modulates Outcomes of Hepatocellular Carcinoma via a Tumor Adaptive Mechanism to Genomic Stress.

Nucleostemin 通过基因组应激的肿瘤适应机制调节肝细胞癌的结果。

• 发表时间: 2020
• 作者: Wang, Junying;McGrail, Daniel J;Bhupal, Parnit K;Zhang, Wen;Lin, Kuan;Ku, Yi;Lin, Tao;Wu, Hongfu;Tsai, Kyle C;Li, Kaiyi;Peng, Cheng;Finegold, Milton J;Lin, Shiaw;Tsai, Robert Y L
• 通讯作者: Tsai, Robert Y L

Balancing self-renewal against genome preservation in stem cells: How do they manage to have the cake and eat it too?

平衡自我更新与干细胞基因组保存：它们如何做到鱼与熊掌兼得？

• DOI: 10.1007/s00018-016-2152-y
• 发表时间: 2016-05
• 期刊: Cellular and Molecular Life Sciences
• 影响因子: 8
• 作者: Tsai, Robert Y. L.