Role of miR-124a in HTLV-I oncogenesis

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）的病原，是一种以病毒感染CD4+T细胞克隆扩增为特征的侵袭性致命疾病。据估计，全世界有2000万至3000万人感染HTLV-I。ATL是预后最差的疾病之一，急性期的中位生存期为6-9个月，淋巴瘤期为10-12个月。总的来说，接受各种化疗或放疗方案治疗的ATLL患者的生存是有限的，因为大多数患者复发并伴有侵袭性肿瘤并在此后不久死亡。HTLV-I肿瘤发生的分子基础尚不清楚。低发病率和发病前的长潜伏期表明，宿主感染细胞的遗传改变的积累是疾病进展所必需的。我们发现，在ATL细胞中，microRNA miR-124a通过其启动子的表观遗传沉默被特异性下调。在本提案中，我们将进一步表征miR-124a对HTLV-I感染细胞增殖和存活的作用。然后，我们将研究miR-124a与HTLV-I转化细胞中其他失调控的microRNA之间的潜在合作关系。由于miR-124a在许多人类癌症中下调，因此这一建议具有广泛的潜在意义。

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.