Elucidating the role of microRNAs in the initiation of multiple myeloma

阐明 microRNA 在多发性骨髓瘤发生中的作用

• 批准号: 9327886
• 负责人: Jianjun Zhao
• 金额: $ 24.9万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327886
• 关键词: 3' Untranslated Regions; Age; Antisense Oligonucleotides; Apoptosis; Autologous Stem Cell Transplantation; B-Lymphocytes; Bone Marrow; CDKN1C gene; Cancer Patient; Cell Compartmentation; Cell Cycle; Cell Differentiation process; Cell physiology; Cells; Clinical; Clinical Trials; Code; Cultured Tumor Cells; Data; Development; Dexamethasone; Diagnosis; Disease; Dose; Early Diagnosis; Event; Family; Gene Components; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Hematologic Neoplasms; Human; In Vitro; Individual; Lesion; Lytic; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mentors; Messenger RNA; MicroRNAs; Molecular Genetics; Molecular Target; Monoclonal Gammapathies; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mus; Names; Oncogenes; PTEN gene; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phase; Plasma Cells; Play; Pre-Clinical Model; Precancerous Conditions; Prognostic Marker; Proteins; RNA; Regulation; Research; Resistance; Role; Sampling; Serum; Specimen; Structure of germinal center of lymph node; TP53 gene; Therapeutic; Therapeutic Intervention; Transgenic Mice; Transgenic Organisms; Untranslated RNA; Work; Xenograft procedure; base; bone; cancer stem cell; chemotherapy; diagnostic biomarker; experimental study; gene product; improved; improved outcome; in vivo; inhibitor/antagonist; mouse model; novel; novel strategies; novel therapeutics; overexpression; pre-clinical; public health relevance; targeted treatment; therapeutic target; tool; tumor; tumor progression

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a cancer characterized by colonial proliferation of plasma cells in bone marrow, lytic bone lesions, and serum monoclonal gammopathy. MM is the 2th most frequent hematological cancer in the US. The median survival span of MM patients is only 2~6 years, despite treatment either with conventional chemotherapy with or without high-dose therapy/autologous stem cell transplantation, or with new drugs which have novel mechanisms. Increasingly evidence shows that a super family of small (20~24 nt) non-coding RNAs named microRNAs (miRNAs) are involved in cell differentiation, proliferation and apoptosis by targeting 3'UTR of mRNAs of protein coding genes, and therefore involved in cancer pathogenesis, including MM. In our previous work, we identified that two miRNA super families were most significantly deregulated in human MM and cancer stem cells (CSCs) compartment: down-regulated miR-30s, and up-regulated miR-222-221. Moreover, miR-222-221 are the most up-regulated miRNAs in MM. Based on our preliminary data, over- expression of miR-222-221 targets PUMA leads to dexamethasone resistance and CSC accumulation in MM. Nevertheless, it remains unexplored whether miR-222-221 will initiate MM and promote malignant progression in vivo. Accumulating evidence also implicated that miR-222-221 plays a role as oncogene in vitro in a large variety of other cancers, but a causal role for miR-222-221 in the initiation of MM has not been demonstrated. Based on our observation in MM, we hypothesize that this miRNA family may contribute to the initiation and progression of MM. We propose to combine genetic and pharmacological approaches to study the role of miR- 222-221 in MM initiation and its potential to be a therapeutic target. Firstly, we will explore the functioal significance of miR-222-221 and their regulatory network in MM by using the clinical samples and several computational approaches to construct a network of miRNA-mRNA interactions (Aim 1). In parallel, we will functional characterize the role miR-222-221 in MM proliferation, apoptosis and CSC formation by using two preclinical mouse models. One is a conditional transgenic mouse model: Tg:(miR-222-221, AID-Cre mice), which will active miR-222-221 expression in late stage of B cells and plasma cell. Another one is a preclinical human MM cell bearing mouse model (Aim 2). Furthermore, we will functional verify the microRNAs key downstream genes and to evaluate the potential of miR-222-221 as a therapeutic target in vitro and in vivo (Aim 3). Our long-term goal is to understand the role of miRNAs in regulating MM initiation, and to develop new candidate therapies for this malignant disease.

描述（由申请人提供）：多发性骨髓瘤（MM）是一种癌症，其特征是骨髓，裂解骨病变和血清单克隆性肾上腺病中血浆细胞的殖民地增生。 MM是美国第2大最常见的血液学癌症。 MM患者的中位生存跨度仅为2至6年，尽管有或不接受高剂量治疗/自体干细胞移植或具有新型机制的新药进行了常规化学疗法治疗。越来越多的证据表明，通过靶向蛋白质编码基因的3'UTR，参与细胞分化，增殖和凋亡，其中一个小的（20〜24 nt）非编码RNA（miRNA）参与了细胞分化，增殖和凋亡，因此参与了包括MM在内的癌症病原体。在我们以前的工作中，我们确定了两个miRNA超级家族在人MM和癌症干细胞（CSC）室中最显着放松管制：下调的miR-30和上调的miR-222-221。此外，miR-222-221是mm中最上调的miRNA。基于我们的初步数据，miR-222-221的过度表达靶标PUMA导致地塞米松的耐药性和CSC在MM中的积累。然而，MiR-222-221是否会启动MM并促进体内恶性进展，仍然没有探索。积累的证据也暗示miR-222-221在许多其他癌症中在体外起癌基因的作用 尚未证明MM的启动。根据我们在MM中的观察结果，我们假设该miRNA家族可能有助于MM的启动和进展。我们建议结合遗传和药理方法，以研究miR-222-221在MM启动中的作用及其成为治疗靶点的潜力。首先，我们将通过使用临床样品和几种计算方法来构建miRNA-MRNA相互作用网络（AIM 1），探讨MIR-222-221及其在MM中的调节网络的功能意义。同时，我们将使用两种临床前小鼠模型来表征MIR-222-221在MM增殖，凋亡和CSC形成中的作用。一个是条件转基因小鼠模型：TG ：（ miR-222-221，aid-cre小鼠），它将在B细胞和浆细胞的后期中积极miR-222-221表达。另一个是临床前人类MM细胞轴承小鼠模型（AIM 2）。此外，我们将功能验证下游基因的microRNA键，并评估miR-222-221作为体外和体内治疗靶标的潜力（AIM 3）。我们的长期目标是了解miRNA在调节MM启动中的作用，并为这种恶性疾病开发新的候选疗法。

项目成果

Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma.

• DOI: 10.1038/s41375-018-0104-2
• 发表时间: 2018-10
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Hu Y;Lin J;Fang H;Fang J;Li C;Chen W;Liu S;Ondrejka S;Gong Z;Reu F;Maciejewski J;Yi Q;Zhao JJ
• 通讯作者: Zhao JJ