Pilot Project 1 (Liver Cancer)

试点项目 1（肝癌）

• 批准号: 10302580
• 负责人: DEVANAND SARKAR
• 金额: $ 8.49万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10302580
• 关键词: African American; Anti-Inflammatory Agents; Antineoplastic Agents; Biological Assay; Blueberries; Cancer Center; Cancer Etiology; Cell Line; Cessation of life; Chronic; Data; Data Set; Databases; Development; Dietary Component; Disease; Ethnic Origin; Evaluation; Exhibits; Gene Expression; Genes; Ginger; Growth; Hepatitis C; Hepatitis C virus; IFI6 gene; ISG15 gene; Incidence; Inflammation; Inflammatory; Interferon Type I; Interferons; Knowledge; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Mediating; Molecular; Molecular Profiling; Not Hispanic or Latino; Nutraceutical; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Phosphotransferases; Pilot Projects; Play; Preventive; Primary carcinoma of the liver cells; Property; RNA analysis; Race; Research Training; Risk Factors; Role; Running; STAT1 gene; STAT2 gene; Sampling; Signal Pathway; Signal Transduction; Survival Rate; The Cancer Genome Atlas; Therapeutic; Tissue Banks; Tissue-Specific Gene Expression; Toxic effect; Training Programs; Translating; Universities; Virginia; Virulence; anti-cancer; base; black patient; cancer health disparity; caucasian American; chemotherapy; cytokine; dietary; differential expression; effective therapy; efficacy evaluation; established cell line; gain of function; genetic signature; innovation; insight; loss of function; mortality; novel; overexpression; patient derived xenograft model; prevent; racial disparity; response; side effect; targeted treatment; transcriptome sequencing; tumor; tumorigenesis

PILOT PROJECT 1: PROJECT SUMMARY Hepatocellular carcinoma (HCC) is a highly fatal disease with mortality running parallel to its incidence. Lack of effective treatment for advanced HCC calls for insights into the molecular pathogenesis of HCC and development and evaluation of novel, targeted therapeutic strategies. For HCC patients, there is a statistically significant increase in incidence and mortality and a decrease in 5-year survival rates in African American (AA)/Black patients compared to non-Hispanic (white) patients. There is a gap of knowledge in our understanding of the molecular mechanism underlying the HCC racial disparity between AA/Black and white patients. Analysis of RNA-sequencing (RNA-Seq) data in the TCGA database and RNA-Seq on HCC tumor samples revealed that in both datasets the only pathway that showed statistically significant activation in AA/Black patients is the type I interferon (IFN-I) signaling pathway. This pathway is activated by Hepatitis C virus (HCV) infection, a major risk factor for HCC. Correction of the differential gene expression data based on HCV status still identified activation of IFN-I signaling pathway in AA/Black HCC patients indicating that the observed findings in AA/Black patients are independent of HCV status. HCC is a disease of chronic inflammation and IFN-Is function as pro- inflammatory and immunosuppressive cytokines, establishing the rationale for studying them. We hypothesize that persistent activation of the IFN-I signaling pathway might be a key determinant of racial disparity in AA/Black HCC patients, and even if IFN-I-inducible genes (ISGs) are induced in response to HCV infection in AA/Black patients their expression is maintained—contributing to HCC development and virulence. In this study, the role of a 4-ISG signature in regulating HCC in white and AA/Black patients will be systematically analyzed using HCC patient-derived xenograft (PDX) cell lines and the efficacy of dietary anti-inflammatory compounds in inhibiting them will be evaluated. The proposed studies will help develop a targeted therapeutic approach for AA/Black HCC patients thus having both mechanistic and therapeutic significance and innovation. Successful completion of the proposed studies will create new avenues for effective treatment of scores of AA/Black HCC patients for whom currently no effective treatment option is available.

试点项目1：项目摘要 肝细胞癌（HCC）是一种高致死性疾病，死亡率与其发病率平行。缺乏 晚期肝癌的有效治疗需要深入了解肝癌的分子发病机制和发展 和评价新的、有针对性的治疗策略。对于HCC患者， 非裔美国人（AA）/黑人的发病率和死亡率增加，5年生存率下降 与非西班牙裔（白色）患者相比。在我们的理解中有一个知识的空白。 AA/黑人和白色患者之间HCC种族差异的分子机制。分析 TCGA数据库中的RNA测序（RNA-Seq）数据和HCC肿瘤样本的RNA-Seq显示， 在两个数据集中，AA/黑人患者中显示统计学显著激活的唯一途径是I型 干扰素（IFN-I）信号通路。该途径被丙型肝炎病毒（HCV）感染激活，这是一个主要的风险， HCC的因素。基于HCV状态的差异基因表达数据的校正仍然确定激活 在AA/黑人HCC患者中IFN-1信号通路的变化表明在AA/黑人患者中观察到的结果 与HCV状态无关。HCC是一种慢性炎症性疾病，IFN-γ作为促细胞增殖剂发挥作用。 炎症和免疫抑制细胞因子，建立了研究它们的基本原理。我们假设 IFN-1信号通路的持续激活可能是AA/Black中种族差异的关键决定因素。 HCC患者，即使IFN-I诱导基因（ISG）在AA/Black中对HCV感染的应答中被诱导， 在HCC患者中，它们的表达是不稳定的，这有助于HCC的发展和毒力。在这项研究中， 在白色和AA/黑人患者中调节HCC的4-ISG特征将使用HCC进行系统分析。 患者来源的异种移植物（PDX）细胞系以及膳食抗炎化合物抑制肿瘤细胞增殖的功效 他们将被评估。拟议的研究将有助于开发AA/Black的靶向治疗方法 从而对HCC患者的机理和治疗都具有重要意义和创新。成功完成 这些拟议的研究将为有效治疗AA/黑色HCC患者创造新的途径， 目前没有有效的治疗方法。