The Role of lncRNA MEG3 in Clinically Non-functioning Pituitary Adenomas

lncRNA MEG3 在临床无功能垂体腺瘤中的作用

• 批准号: 9215659
• 负责人: ANNE KLIBANSKI
• 金额: $ 37.7万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-04 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215659
• 关键词: 14q32; Affect; Angiogenesis Inhibition; Animal Model; Anterior Pituitary Gland; Applications Grants; Autophagocytosis; Binding; Blindness; Cancer cell line; Cell Cycle Arrest; Cell Line; Cell Proliferation; Cells; Chromosomes; Clinical; DNA Methylation; Data; Development; Diagnosis; Embryo; Epigenetic Process; Event; Future; G1 Phase; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Histone Deacetylation; Hormones; Human; Hypopituitarism; Inhibition of Cell Proliferation; Intracranial Neoplasms; Investigation; Knockout Mice; Knowledge; Lead; Link; Longevity; MDM2 gene; Mediating; Medical; Molecular; Molecular Profiling; Mus; Mutation; Nature; Neurologic Deficit; Nude Mice; Operative Surgical Procedures; Pathogenesis; Patients; Pituitary Gland; Pituitary Gland Adenoma; Pituitary Neoplasms; Play; Population; Protein p53; Radiation therapy; Research; Resected; Role; Somatic Cell; TP53 gene; Testing; Therapeutic; Tumor Biology; Tumor Suppression; Tumor Suppressor Proteins; Untranslated RNA; X Chromosome; adenoma; angiogenesis; cell transformation; cell type; imprint; in vivo; insight; mouse model; neoplastic cell; novel; pituitary gland development; promoter; public health relevance; tumor; tumor growth; tumor xenograft

 DESCRIPTION (provided by applicant): Human pituitary adenomas represent the most common intracranial neoplasm. Approximately a third of diagnosed pituitary tumors do not hypersecrete hormones, therefore classified as clinically non-functioning adenomas (NFAs). These tumors usually grow large in size, resulting in neurologic deficit and hypopituitarism in patients. The large majority of NFA are derived from gonadotroph cells and cannot be treated medically. Furthermore, the molecular mechanisms causing NFAs are mostly unknown. Therefore, there is an urgent need to investigate molecular events specifically linked to the development of these tumors. Using an X- chromosome linked marker, we discovered that NFA cells are monoclonal in nature, meaning that they are derived from a single somatic cell transformed by genetic or epigenetic mutations. Therefore, identification of such mutations and investigation of the function of affected genes will yield insights into the mechanisms of NFA development. By comparing gene expression between normal pituitaries and NFAs, and subsequent investigations, we identified Maternally Expressed Gene 3 (MEG3) as a novel candidate tumor suppressor in the pituitary. MEG3 is highly expressed in normal pituitary. Its expression is lost only in NFAs, partially due to epigenetic silencing of its promoter, not seen in other pituitary tumor types. Re-expression of MEG3 inhibits tumor cell proliferation and xenograft tumor growth. Strikingly, the products of the MEG3 gene are long non-coding RNAs and function through a well-known tumor suppressor p53. Taken together, we hypothesize that MEG3 uses novel mechanisms to suppress the development of human pituitary NFAs. Therefore, the goal of our study is to determine the in vivo function of the MEG3 gene in suppression of pituitary tumors using animal models and unveil molecular mechanisms of MEG3 tumor suppression. In this grant application, we propose to determine 1) the effects of Meg3 inactivation on the development of pituitary tumors in vivo; 2) mechanisms whereby MEG3 lncRNA suppresses tumor growth and 3) the mechanism of p53 activation by MEG3 lncRNA. The discovery of MEG3 non-coding RNA gene as a candidate tumor suppressor is a critical step in understanding the pathogenesis of human NFAs. The investigation of its function in tumor suppression will broaden our knowledge of the involvement of non-coding RNAs in human tumor biology; and provide opportunities to develop novel medical therapies for human pituitary tumors.

 描述（由申请方提供）：人垂体腺瘤是最常见的颅内肿瘤。大约三分之一的诊断垂体瘤不过度分泌激素，因此被归类为临床无功能腺瘤（NFA）。这些肿瘤通常长得很大，导致患者神经功能缺损和垂体功能减退。绝大多数NFA来源于促性腺激素细胞，不能用药物治疗。此外，引起NFA的分子机制大多是未知的。因此，迫切需要研究与这些肿瘤发展相关的分子事件。使用X染色体连锁标记，我们发现NFA细胞本质上是单克隆的，这意味着它们来源于通过遗传或表观遗传突变转化的单个体细胞。因此，鉴定这些突变和调查受影响的基因的功能将产生深入了解NFA的发展机制。通过比较正常垂体和NFA之间的基因表达，以及随后的研究，我们确定了母亲表达基因3（MEG 3）作为一种新的候选肿瘤抑制基因在垂体。MEG 3在正常垂体中高表达。其表达仅在NFA中丢失，部分原因是其启动子的表观遗传沉默，而在NFA中未观察到。 其他垂体瘤类型MEG 3的再表达抑制肿瘤细胞增殖和异种移植肿瘤生长。引人注目的是，MEG 3基因的产物是长的非编码RNA，并通过众所周知的肿瘤抑制因子p53发挥作用。综上所述，我们假设MEG 3使用新的机制来抑制人类垂体NFA的发展。因此，我们的研究目标是使用动物模型确定MEG 3基因在抑制垂体肿瘤中的体内功能，并揭示MEG 3肿瘤抑制的分子机制。在这项授权申请中，我们建议确定1）Meg 3失活对体内垂体肿瘤发展的影响; 2）MEG 3 lncRNA抑制肿瘤生长的机制; 3）MEG 3 lncRNA激活p53的机制。MEG 3非编码RNA基因作为一种候选抑癌基因的发现是了解人类NFAs发病机制的关键一步。研究其在肿瘤抑制中的功能将拓宽我们对非编码RNA参与人类肿瘤生物学的认识，并为开发人类垂体瘤的新药物治疗提供机会。