Hsp90调控USP8通路在ACTH型垂体瘤中的作用机制研究

ACTH型垂体瘤(库欣病)是一种严重威胁青壮年人生命的神经内分泌疾病，其发病机制仍不太清楚。我们前期研究发现：①USP8(去泛素化酶8)基因突变与ACTH型垂体瘤发生密切相关，62.5%的病人携带USP8(突变位点)；②Hsp90、Hsp70和Hsf1在人ACTH垂体瘤组织中表达升高；③USP8蛋白与Hsp90蛋白能体外结合。由此，我们推测Hsp90参与USP8突变介导的ACTH型垂体瘤生长调控。为此，本研究将重点研究：①Hsp90对USP8基因突变的调控机制；②Hsp90上调垂体EGFR信号通路和ACTH产生的机制。本研究将揭示ACTH型垂体瘤中Hsp90调控USP8基因通路的关键机制，为临床靶向治疗提供理论依据。

Cushing Disease (CD) is ACTH-produced pituitary adenomas that occur predominantly in young adults and puberty with high immortality. However, its pathological mechanism is still not clear. Our preliminary data demonstrate that, 1, mutation of USP8 (deubiqutinase) is closely associated with CD. 62.5% CD patients have the USP8 mutation. Mutation of USP8 can induce EGFR protein stabilization and signal transduction leading upregulation of the ACTH expression; 2, Hsp90 and Hsp70 are upregulated in the CD tumor tissues compared to the parental control; 3, the results of Gst-pull down assay indicate that USP8 can interact with Hsp90 in the ACTH-type cell line. We therefore, hypothesize accordingly that mutation USP8 could be activated by Hsf1-meidated heat shock response, which lead to CD tumor growth. In this grant application, we will focus on: 1, dissection the regulatory mechanism of Hsp90 on mutation USP8; 2, the upregulation of the expression of ACTH and EGFR by Hsp90 pathway in ACTH tumor cell lines. Our aim is to dissect the key regulatory association between Hsf90 and USP8mutation on ACTH tumorigenesis and being targets for potential therapy of ACTH pituitary adenomas.