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）是一种以骨髓中浆细胞集落增殖、溶骨性病变和血清单克隆丙种球蛋白病为特征的癌症。 MM 是美国第二大常见的血液癌症。尽管采用常规化疗联合或不联合大剂量治疗/自体干细胞移植，或采用具有新机制的新药，MM患者的中位生存期仅为2~6年。越来越多的证据表明，一个名为microRNA（miRNA）的小（20~24 nt）非编码RNA超家族通过靶向蛋白质编码基因mRNA的3'UTR参与细胞分化、增殖和凋亡，从而参与癌症的发生发病机制，包括MM。在我们之前的工作中，我们发现两个 miRNA 超家族在人类 MM 和癌症干细胞 (CSC) 区室中最显着失调：下调的 miR-30s 和上调的 miR-222-221。此外，miR-222-221 是 MM 中上调最多的 miRNA。根据我们的初步数据，miR-222-221靶标PUMA的过度表达导致MM中地塞米松耐药和CSC积累。然而，miR-222-221是否会引发MM并促进体内恶性进展仍有待探索。越来越多的证据还表明，miR-222-221 在体外多种其他癌症中发挥癌基因的作用，但 miR-222-221 在 MM 的启动尚未得到证实。根据我们对 MM 的观察，我们假设该 miRNA 家族可能有助于 MM 的发生和进展。我们建议结合遗传和药理学方法来研究 miR-222-221 在 MM 起始中的作用及其作为治疗靶点的潜力。首先，我们将通过使用临床样本和几种计算方法构建 miRNA-mRNA 相互作用网络，探索 miR-222-221 及其调控网络在 MM 中的功能意义（目标 1）。与此同时，我们将通过使用两种临床前小鼠模型来功能性地表征 miR-222-221 在 MM 增殖、细胞凋亡和 CSC 形成中的作用。一种是条件转基因小鼠模型：Tg：（miR-222-221，AID-Cre小鼠），它会激活B细胞和浆细胞晚期的miR-222-221表达。另一种是临床前携带人类 MM 细胞的小鼠模型（目标 2）。此外，我们将功能验证 microRNA 关键下游基因，并评估 miR-222-221 作为体外和体内治疗靶点的潜力（目标 3）。我们的长期目标是了解 miRNA 在调节 MM 起始中的作用，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