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

 描述(申请人提供)：人类脑垂体腺瘤是最常见的颅内肿瘤。大约三分之一的诊断出的脑垂体瘤没有高分泌激素，因此被归类为临床无功能腺瘤(NFA)。这些肿瘤通常长得很大，导致患者出现神经功能障碍和垂体功能减退。绝大多数NFA来自促性腺激素细胞，不能用药物治疗。此外，引起NFAs的分子机制大多尚不清楚。因此，迫切需要研究与这些肿瘤的发生有关的分子事件。使用X染色体连锁标记，我们发现NFA细胞本质上是单克隆性的，这意味着它们来自于通过遗传或表观遗传突变转化的单个体细胞。因此，鉴定这些突变并研究受影响基因的功能将有助于深入了解NFA的发生机制。通过比较正常垂体和NFAs的基因表达，以及随后的研究，我们发现母体表达基因3(MEG3)是一种新的候选肿瘤抑制基因。MEG3在正常脑垂体中高表达。它的表达只在NFAs中丢失，部分原因是其启动子的表观遗传沉默，在 其他类型的脑垂体瘤。MEG3的重新表达可抑制肿瘤细胞的增殖和移植瘤的生长。值得注意的是，MEG3基因的产物是长的非编码RNA，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MEG3使用新的机制来抑制人类垂体NFAs的发展。因此，本研究的目的是通过动物模型研究MEG3基因在体内对垂体肿瘤的抑制作用，揭示MEG3基因抑制肿瘤的分子机制。在这项拨款申请中，我们建议确定1)Meg3失活对体内垂体肿瘤发展的影响；2)MEG3 lncRNA抑制肿瘤生长的机制；3)MEG3 lncRNA激活P53的机制。MEG3非编码RNA基因作为候选抑癌基因的发现是理解人类NFAs发病机制的关键一步。研究其在肿瘤抑制中的作用将拓宽我们对非编码RNA参与人类肿瘤生物学的认识，并为开发治疗人类垂体肿瘤的新药物提供机会。

 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.