gamma-OHPdG as a prognostic biomarker of HCC recurrence and its prevention

γ-OHPdG 作为 HCC 复发及其预防的预后生物标志物

• 批准号: 10475222
• 负责人: FUNG-LUNG CHUNG
• 金额: $ 44.13万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475222
• 关键词: Acrolein; Address; Aftercare; Alcoholic Liver Diseases; Animal Model; Antioxidants; Binding; Biological Assay; Biological Markers; Biopsy Specimen; Blood Vessels; Cancer Etiology; Cessation of life; Clinic; Clinical; DNA; DNA Adducts; Development; Diagnosis; Diethylnitrosamine; Epigallocatechin Gallate; Etiology; Excision; Extrahepatic; FDA approved; Formulation; Future; Goals; Healthcare; Hepatic; Hepatitis B Virus; Hepatitis C virus; Hepatocarcinogenesis; Human; Inbred LEC Rats; Incidence; Inflammation; Intervention Trial; Knockout Mice; Lipid Peroxidation; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Methods; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Nucleotide Excision Repair; Operative Surgical Procedures; Pathway interactions; Patients; Polyphenon E; Polyunsaturated Fatty Acids; Prevention; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Prognosis; Prognostic Marker; Recurrence; Resistance; Risk; Role; Sampling; Stains; TP53 gene; Time; Tissues; Urine; Xeroderma Pigmentosum; adduct; base; cancer recurrence; carcinogenesis; chemotherapy; clinical application; clinical predictors; disorder later incidence prevention; early detection biomarkers; high risk; in vivo; liver biopsy; nonalcoholic steatohepatitis; oxidation; patient population; predictive marker; prevent; recruit; tumor; urinary

Hepatocellular carcinoma (HCC) is the third leading cause of cancer–related deaths worldwide, mainly because of its poor prognosis. A valid and reliable mechanism-based prognostic biomarker is urgently needed. γ-Hydroxy-1,N2-propanodeoxyguanosine (γ-OHPdG) is an endogenous mutagenic DNA adduct derived from lipid peroxidation (LPO). We studied the relationship between hepatic γ-OHPdG and hepatocarcinogenesis in three animal models and the potential of γ-OHPdG to be used as a prognostic biomarker for recurrence in HCC patients after surgical resection. Tumor bioassays were conducted in Xeroderma pigmentosum group A knockout mice (Xpa-/-), diethylnitrosamine (DEN)-injected mice, and Long-Evans Cinnamon (LEC) rats, and all are prone to HCC development. We found that the increased γ-OHPdG levels in liver DNA correlated with HCC development in all three animal models. Furthermore, Theaphenon E treatment significantly decreased γ-OHPdG levels in the liver DNA of Xpa-/- mice, and this decrease was closely associated with its remarkable effect to reduce HCC incidence (from 100% to 14%). Theaphenon E also effectively inhibited HCC development in DEN-injected mice. Using two independent sets of clinical samples from 90 and 45 HCC patients, our studies demonstrated that higher levels of γ-OHPdG in HCC biopsy specimens, detected by immunohistochemical staining , are strongly associated with low survival (p<0.0001) and low recurrence-free survival (p=0.007), respectively. These results support γ- OHPdG as a promising biologically relevant biomarker for predicting the risk of HCC and its recurrence. In this proposal, we propose in Aim 1 to extend these exciting findings to include a larger patient population to further address questions on γ-OHPdG’s relationships with (1) the underlying etiology of HCC, e.g. HBV, HCV, alcoholic liver disease, and non-alcoholic steatohepatitis (NASH) and (2) clinical predictors for aggressiveness, e.g. differentiation, HCC stage, vascular invasion, and extra-hepatic metastasis. We also want to compare its levels with those of the adjacent non-tumorous tissues and to examine the tumor mutation load. In Aims 2 and 3, we will develop a non-invasive method for detecting γ-OHPdG in human urine. Our hypothesis is that the adduct levels in urine reflect those in liver DNA. In Aim 4, we will conduct an intervention trial with Polyphenon E, an FDA approved equivalent of Theaphenon E, to prevent HCC recurrence in high risk patients identified with high liver γ-OHPdG. Our long-term goal is to develop γ-OHPdG as a prognostic biomarker for HCC and its recurrence for intervention trials.

肝细胞癌（HCC）是全球与癌症相关的死亡的第三大主要原因， 主要是因为它的预后不佳。有效且可靠的基于机制的预后 迫切需要生物标志物。 γ-羟基-1，N2-丙氧化瓜烷（γ-OHPDG）是 源自脂质过氧化（LPO）的内源性诱变DNA加合物。我们研究了 三种动物模型中的肝γ-OHPDG与肝癌发生之间的关系 γ-OHPDG的潜力被用作HCC患者复发的预后生物标志物 手术切除后。肿瘤生物测定是在静脉表色素A组中进行的 敲除小鼠（XPA - / - ），二乙基硝基胺（DEN）注射的小鼠和长evans Cinnamon （LEC）大鼠，所有大鼠都容易发生HCC。我们发现增加的γ-OHPDG 肝DNA的水平与所有三种动物模型中的HCC发育相关。此外， theaphenon e处理可显着提高XPA的肝脏DNA的γ-OHPDG水平 - / - 小鼠，这种下降与其显着效果密切相关以减少HCC 发病率（从100％到14％）。剧院E还有效地抑制了HCC的发展 注射的小鼠。使用来自90和45 HCC的两组独立的临床样本 患者，我们的研究表明，HCC活检标本中较高水平的γ-OHPDG， 通过免疫组织化学染色检测到，与低存活密切相关 （p <0.0001）和低复发生存率（p = 0.007）。这些结果支持γ- OHPDG作为承诺与生物学相关的生物标志物，以预测HCC及其其风险 复发。在此提案中，我们建议在目标1中扩展这些令人兴奋的发现，以包括 更大的患者人群进一步解决有关γ-OHPDG与（1）的关系的问题 HCC的基础病因，例如HBV，HCV，酒精性肝病和非酒精 脂肪性肝炎（NASH）和（2）侵略性的临床预测因子，例如分化，HCC 阶段，血管侵袭和外部转移。我们还想将其水平与 相邻的非肿瘤组织的那些，并检查肿瘤突变载荷。在目标2中 3，我们将开发一种用于检测人尿中γ-OHPDG的非侵入性方法。我们的 假设是尿液中的加合物水平反映了肝脏DNA中的加合物。在AIM 4中，我们将进行 与FDA批准的相当于剧院E的Polyphenon E进行的干预试验 防止高风险患者识别出高肝γ-OHPDG的HCC复发。我们的长期 目标是将γ-OHPDG作为HCC的预后生物标志物开发 干预试验。