MEN1基因调控Wnt/β-catenin信号通路在肾上腺皮质癌进展中的作用机制及靶向治疗研究

肾上腺皮质癌（ACC）是一类进展迅速的罕见内分泌恶性肿瘤，发生率低而致死率高，MEN1是ACC的重要基因变异，但其在ACC进展中的作用机制尚不清楚。我们前期通过家系研究发现ACC中存在MEN1基因变异和β-catenin核染色阳性，干扰MEN1基因可降低β-catenin磷酸化水平，且β-catenin抑制剂能逆转MEN1缺失导致的细胞增殖和侵袭。据此我们提出假说：MEN1可介导β-catenin磷酸化调控Wnt/β-catenin信号通路、抑制ACC进展。本项目拟从分子、细胞和动物水平等多层次对MEN1调控Wnt/β-catenin信号通路在ACC进展中的作用及机制开展深入研究，并利用β-catenin的小分子抑制剂干预MEN1缺失的ACC，探讨ACC个体化药物治疗的靶点。本研究首次提出MEN1可介导β-catenin磷酸化抑制ACC进展，有望为ACC的治疗提供新的切入点和理论依据。

Adrenocortical carcinoma (ACC) is a kind of rare endocrine malignant tumor with rapid progress, which has a low incidence and high mortality. MEN1 is one of the most common gene variations of ACC. Our previous study found that there were MEN1 gene mutation and positive immunohistochemistry staining of β-catenin in ACC. Cell function experiment showed that interfering with MEN1 gene can reduce the phosphorylation level of β-catenin, and β-catenin inhibitor can rescue the cell proliferation and invasion caused by MEN1 gene deletion. Therefore, we hypothesized that MEN1 could mediate β-catenin phosphorylation to regulate Wnt/β-catenin signaling pathway and inhibit ACC progression. In order to verify this hypothesis, we intend to systematically study the role and mechanism of MEN1 in regulating Wnt/β-catenin signaling pathway in ACC progress at the molecular, cellular and animal levels, and use small molecule drugs targeting Wnt/β-catenin signaling pathway to MEN1-deficient ACC, so as to explore the target of individualized drug therapy for ACC. This study is the first to propose that MEN1 can mediate β-catenin phosphorylation/degaradation to inhibit the progression of ACC, which is expected to provide the prospects of specific and effective therapeutic treatment.