BiP/IRE1α通路激活介导PC1/3降解促进静默性ACTH细胞腺瘤发生、发展的机制研究

静默性促肾上腺皮质激素细胞瘤(SCA)属于高风险垂体腺瘤，呈快速侵袭性生长，术后复发率高。SCA发生、发展的机制仍不清楚，制约了临床疗效的进一步提高。SCA的主要临床特征是ACTH分泌正常（生化静默）和肿瘤恶性程度高，我们在前期研究中发现SCA中BiP/IRE1通路激活，并证实该通路不仅通过调控HRD1介导PC1/3蛋白的降解影响肿瘤ACTH分泌导致生化静默，同时BiP的激活还可以促进肿瘤侵袭。因此本项目拟在前期基础上，针对SCA生化静默和恶性进展的原因和机制进行深入研究，阐释HRD1调控PC1/3蛋白泛素化降解影响ACTH分泌的机制；研究BiP/IRE1α通路激活上调HRD1表达和促进肿瘤侵袭的机制，并评估该通路相关分子的表达对SCA术前诊断和预后评估的有效性。研究结果将系统阐释SCA生化静默和恶性进展的原因和机制，为SCA新药研发、新型分子标志物和治疗靶点选择提供理论依据和实验基础。

Silent corticotropin adenoma (SCA) is a kind of high-risk pituitary adenoma, which often presents invasive growth with high recurrence. The mechanism of tumorgenesis and development of SCA is still unclear, which restricts the further improvement of clinical efficacy. The main clinical characteristics of SCA are normal ACTH secretion (biochemical silence) and high tumor malignancy. We found that the interaction between HRD1 and PC1 /3 protein in SCA could affect the ACTH secretion, and the increase of BiP was related to the tumor malignancy. So this project aims to study the mechanism of HRD1 regulating PC1/3 protein degradation and affecting ACTH secretion, to explain the mechanism of the key pathway of ERS, BiP/IRE1α-HRD1 pathway, ubiquitination/degradation of PC1/3. And to study the mechanism of BiP promoting proliferation and invasion of SCA, and to explore the effectiveness of key molecules of BiP/IRE1α pathway as a molecular marker in predicting tumor prognosis. The result of this project will initially clarify the cause and mechanism of biochemical silence and malignant progress of SCA, and provide theoretical basis and experimental basis for drug development, new molecular markers and treatment target selection of SCA.