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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：高级肿瘤对DNA损伤诱导的化学治疗剂（C/TS）的耐药性是癌症死亡率的主要原因。肝细胞癌（HCC）以其对C/TS的先天抵抗而闻名，但潜在的机制尚不清楚。最近的研究开始涉及通知，即后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）修复途径。我的小组研究了一种由茎和癌细胞增强的蛋白质控制的称为核叶蛋白（NS）的自我更新机制。最近，我们发现了NS在促进HR修复和保护癌细胞免受复制引起的DNA损伤的关键活性。我们还发现，NS在HEP3B（人HCC）细胞和后期二乙基硝基胺（DEN）诱导的小鼠HCC中高度表达。该R03应用的目的是获取数据以支持NS在人HCC样品中的临床相关性及其在通过HR修复中赋予HCC耐药性中的潜在作用。我们假设NS表达与人类HCC的恶性肿瘤相关，并且NS耗竭将损害基于HR的双链断裂（DSB）修复（DSB）修复和HCC细胞的化学抗性特性。该假设是基于以下原因提出的：1）在HEP3B细胞和DEN诱导的HCC中，NS表达在晚期癌中被显着上调； 2）需要NS维持HEP3B细胞的连续增殖； 3）NS促进基于HR的修复并防止乳腺癌（MDA-MB-231）和骨（U2OS）肿瘤细胞的基因组损伤； 4）HR缺乏症是敏感的乳房，卵巢，前列腺和胰腺癌对C/TS的敏感性。为了检验我们的假设，将追求三个具体目标。 AIM＃1将表征的临床相关性 NS在人类HCC中。 AIM＃2将确定NS部署对HR基于HR的DSB修复的影响。 AIM＃3将确定NS在介导HCC耐药性中的作用。作为该应用的结果，我们将通过显示人类HCC样品中NS表达的增加或失调，确定NS的临床重要性，定义NS表达与患者的临床结果之间的关系，并提供功能证据，以支持NS在促进HR基于HR基于HR基于HR的HCC细胞中的作用，以促进HCC细胞中的HCC细胞中的所有均具有重要的PRELINALILIAL PRELINALINIL PRELIMILIAL PRELIMILIAL PRELIMINAL PRELIMINAL PRELIMINAL PRELIMINAL PRELIMINAL PRELIMINAL PRESINER DEUTISTRIMINAL DEUTRUINILIL RESSIFIRISRINED RESSIDINDRES RESS 11。如果我们的假设被证明是正确的，它将影响我们对HCC细胞如何适应过度活跃状态并避免致命的基因组不稳定性的知识，HCC如何发展化学抗性的先天特性，以及HCC是否可以通过NS消融对C/TS对C/TS敏感。鉴于HCC的肝癌发生和异质性的复杂性，将C/T与靶向癌细胞使用的常见自适应机制的治疗相结合，提供了一种有吸引力的策略，可提高C/TS的效率和耐受性。