AMPK通过磷酸化ATF2调控生长激素腺瘤增殖机制的研究

垂体生长激素腺瘤部分患者目前缺乏有效的药物治疗，针对其发病机制进行深入研究能够更好的治疗疾病。AMPK调节磷酸化蛋白在肿瘤增殖中的作用已被阐述，但在生长激素腺瘤中的作用及机制还未有报道。本课题组前期工作对生长激素腺瘤磷酸化蛋白质组学进行深入研究，发现生长激素腺瘤与对照组间差异表达的磷酸化蛋白主要富集在AMPK信号通路，且该通路中ATF2的112丝氨酸位点磷酸化水平在生长激素腺瘤中显著降低，提示其可能具有重要作用。体外试验证实激活AMPK能够抑制GH3细胞增殖和分泌。目前，AMPK蛋白通过p-ATF2调节生长激素腺瘤发生发展的机制还未见报道。本研究从组织、细胞及动物模型多层面探讨AMPK如何通过ATF2的112位点磷酸化调控肿瘤增殖的机制，并通过组织芯片筛查ATF2的112位点对肿瘤激素分泌、耐药及预后的影响，进一步探索生长激素腺瘤的发病机制，可为疾病治疗提供潜在靶点。

To date, there were no effective drugs for some of the somatotroph adenomas patients. A better understanding of the pathological mechanism of somatotroph adenomas is an effective way for the treatment. There were reports about the function of phosphoproteins regulated by AMPK in tumor growth, however, its effects on somatotroph adenomas is still unknown. In our preliminary study, we investigated the phosphoproteomics profiling of somatotroph adenomas and found the differently expressed phosphoproteins were mainly enriched in AMPK signaling pathway in somatotroph adenomas. ATF2 (ser112) which enriched in AMPK signaling pathway had the lower phosphorylation level in somatotroph adenomas compared to normal controls, indicating the key role of ATF2 (ser112). The in vitro experiment proved that activation of AMPK can inhibit the tumorigenesis and secretion of GH3 cells. However, the potential mechanism of AMPK promoting the growth of somatotroph adenomas by targeting p-ATF2 is unclear. In this study, we explore the mechanism of AMPK on cell growth and migration by targeting p-ATF2 and the downstream molecules, and clarify the effects of p-ATF2 on hormone secretion, resistance and prognosis. This study reveals the pathogenesis of somatotroph adenomas and provides a potential therapeutic target for somatotroph adenomas.