LRP16对垂体泌乳素瘤的调节作用及其机制研究

Prolactinomas are the most common secreting pituitary adenomas which can cause intracranial high pressure and endocrine disorders, leading to infertility. Studies suggested that estrogen exposure was the main contributory factors for the development of prolactinoma, but the specific molecular mechanism responsible was unclear. LRP16 is a novel gene which was cloned by our group in 1999. It has been shown that LRPI6 was an estrogen-induced gene through its receptor a (ERa) and the expression of LRP 16 gene was closely linked to the progress of estrogen-related tumors (e.g. breast cancer). Recently, we initially found that the expression of LRP16 in prolactinomas was significantly increased, and correlated with the expression of prolactin gene, ERα, PCNA and Ki-67, suggesting that LRP16 may be the key regulatory molecule in the progress of prolactinoma. In this project we will: 1) to verify the relationship between the expression of LRP16 gene and tumor biological characteristics and protein expression of prolactinoma by rat prolactinoma model; 2) to investigate the impact of LRP16 expression on the cell proliferation, invasion and prolactin secretion of MMQ cell lines by the use of cell biology and molecular biology; 3) to explore the possible molecular mechanisms of LRP16 responsible for the progress of prolactinomas. The significance of this research project will be not only to identify the role of LRP16 in the development of prolactinoma but also to provide possible new molecular targets for the future treatment of refractory invasive prolactinoma.

泌乳素瘤是发病率最高的垂体功能性肿瘤，可造成颅内压迫及内分泌紊乱，导致不孕不育。研究认为雌二醇暴露是其主要诱因之一，但是具体分子机制未明。LRP16是本课题组首先克隆的一个雌激素受体α(ERα)反应性基因，既往研究表明其表达与激素相关肿瘤(如乳腺癌)进展密切关联。近期，我们初步发现LRP16在泌乳素瘤中表达明显增高，并与泌乳素基因、ERα、PCNA及Ki-67表达明显相关，提示LRP16可能是调控泌乳素瘤进展的关键分子。本项目将：1)通过泌乳素瘤大鼠模型研究LRP16基因表达与肿瘤生物学性状及相关蛋白表达的相关性；2)采用细胞生物学及分子生物学技术研究LRP16对泌乳素瘤细胞增殖、侵袭及泌乳素分泌功能的影响；3)探讨LRP16影响泌乳素瘤增殖、侵袭的可能分子机制。本项目研究的意义不仅在于明确LRP16在泌乳素瘤发生发展中的作用，并为未来难治性和侵袭性泌乳素瘤的治疗提供可能的新分子靶点。

垂体泌乳素瘤是颅内发病率最高的功能性肿瘤，其发病机制不明，LRP16是课题组首先发现的一个和雌激素相关性肿瘤有关的基因。本课题拟探索LRP16的表达和泌乳素瘤发病进展的关系。本课题的研究内容：1)通过泌乳素瘤大鼠模型研究LRP16基因表达与肿瘤生物学性状及相关蛋白表达的相关性；2)收集临床上明确的垂体泌乳素瘤患者，研究泌乳素基因、ERα、PCNA及Ki-67表达的相关性；3)在细胞层面，采用细胞生物学及分子生物学技术研究LRP16对泌乳素瘤细胞增殖、侵袭及泌乳素分泌功能的影响；4)探讨LRP16的下调表达对泌乳素瘤症状是否有明显缓解。本项目主要研究结果如下：1）SD大鼠垂体泌乳素瘤模型成功，雌激素与雌激素受体拮抗剂不用剂量分别作用后，肿瘤形成与雌激素拮抗剂有剂量依赖性；2）实验组血清泌乳素水平以及垂体重量明显高于对照组，免疫组化和流式细胞仪结果显示ERα在泌乳素瘤的成瘤过程中起着十分重要的作用，宏观上促进成瘤微观上影响细胞周期的变化，与此同时LRP16在泌乳素瘤组织中也呈高表达，且二者变化趋势同步；3）当LPR16水平被抑制后，ERα的表达水平便随之下降而且被抑制的程度也和LRP16同步，并且细胞的分泌能力也下降。这为临床上通过抑制LRP16治疗垂体泌乳素瘤奠定了基础。