Role of miR-124a in HTLV-I oncogenesis

miR-124a 在 HTLV-I 肿瘤发生中的作用

基本信息

批准号：
8189473
负责人：
CHRISTOPHE P NICOT
金额：
$ 19.58万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8189473
关键词：
Acute Adult Affect Apoptotic BCL2 gene Biological Biological Assay CD4 Positive T Lymphocytes Cell Cycle Cell Proliferation Cell Survival Cells Clonal Expansion Data Disease Disease Progression Down-Regulation Epigenetic Process Gene Targeting Genome Growth Human Human T-lymphotropic virus 1 Hypermethylation Incidence Infection Lymphoma Lymphomagenesis Lymphoproliferative Disorders Malignant Neoplasms Mediating MicroRNAs Molecular Mutation Oncogenic Onset of illness Outcome Pathogenesis Pathway interactions Patients Phase Process Radiation therapy Regimen Relapse Reporting Role STAT3 gene Site T-Cell Leukemia Viral Viral Genome Virus Virus Diseases Virus Replication base cell transformation cellular targeting chemotherapy human disease in vitro Assay leukemia metaplastic cell transformation new therapeutic target novel outcome forecast prognostic promoter small hairpin RNA tumor tumorigenesis vector

项目摘要

DESCRIPTION (provided by applicant): Human T-cell Leukemia Virus type 1 (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL), an aggressive and fatal disease characterized by a clonal expansion of virus-infected CD4+T cells. It is estimated that 20 to 30 million people worldwide are infected with HTLV-I. ATL has one of the poorest prognoses, with a median survival of 6-9 months in the acute phase and 10-12 months in the lymphoma phase. Overall, survival of ATLL patients treated with various chemotherapy or radiotherapy regimens is limited, as most patients relapse with aggressive tumors and succumb shortly thereafter. The molecular basis of HTLV-I oncogenesis is not well understood. The low incidence and long latency before the onset of the disease suggest that accumulation of genetic alterations of host infected cells is required for disease progression. We have found that microRNA miR-124a is specifically down-regulated through epigenetic silencing of its promoter in ATL cells. In this proposal, we will further characterize the role of miR-124a on the proliferation and survival of HTLV-I infected cells. We will then study the potential cooperation between miR-124a and other microRNA deregulated in HTLV-I transformed cells. Since miR-124a is down regulated in many human cancers, this proposal has the potential for broad implications. PUBLIC HEALTH RELEVANCE: This application proposes to investigate the mechanism by which epigenetic silencing of miR- 124a occurs in HTLV-I infected cells and adult T-cell leukemia (ATL), a fatal lymphoproliferative disease. Since similar changes are also observed in various human cancers, our studies may offer new therapeutic targets for the treatment of human cancers.

描述（由申请人提供）：人类T细胞白血病病毒1型（HTLV-I）是成人T细胞白血病（ATL）的病因，这是一种侵略性和致命疾病，其特征是病毒感染的CD4+T细胞的克隆扩张。据估计，全世界有20至3000万人感染了HTLV-I。 ATL具有最差的预后之一，急性期的中位存活率为6-9个月，在淋巴瘤期10-12个月。总体而言，通过各种化学疗法或放射治疗方案治疗的ATLL患者的存活率有限，因为大多数患者患有侵袭性肿瘤，并在此后不久屈服。 HTLV-I肿瘤发生的分子基础尚不清楚。疾病发作之前的发病率和长潜伏期表明，疾病进展需要宿主感染细胞的遗传改变的积累。我们发现，通过表观遗传沉默的ATL细胞中的启动子的表观遗传沉默，microRNA miR-124a被特异性下调。在此提案中，我们将进一步表征miR-124a在HTLV-I感染细胞的增殖和存活中的作用。然后，我们将研究miR-124a和其他在HTLV-I转化的细胞中失调的microRNA之间的潜在合作。由于MiR-124a在许多人类癌症中受到调节，因此该提案具有广泛影响的潜力。公共卫生相关性：该应用建议研究MiR-124A的表观遗传沉默在HTLV-I感染细胞和成人T细胞白血病（ATL）中发生的机制，这是一种致命的淋巴细胞增生性疾病。由于在各种人类癌症中也观察到了类似的变化，因此我们的研究可能为治疗人类癌症提供新的治疗靶点。