CK2诱导的PTEN蛋白Ser380/Thr382/383位点磷酸化激活PI3K/Akt信号通路在胃癌形成、生长及转移中的作用及机制

抑癌基因PTEN在胃癌中的失活机制是近来研究的热点。在前期系列研究中，我们发现胃癌中PTEN失活的一种新机制- - PTEN蛋白Ser380/Thr382/383位点磷酸化失活。该特异位点磷酸化通常由CK2诱导，将使PTEN丧失磷酸酶活性，进而失去对PI3K/Akt通路的抑制，使肿瘤易感性增加；而在胃黏膜癌变中亦常存在CK2和PI3K/Akt通路的活化。据此，我们推测：在胃黏膜癌变中，CK2可使PTEN蛋白该特异位点磷酸化失活，进而激活PI3K/Akt通路，引起细胞生物学异常，参与胃癌的发生、发展。因此，项目拟通过建立该特异位点磷酸化失活的胃癌细胞模型和裸鼠模型，从整体、细胞和分子水平深入研究胃黏膜癌变中CK2对PTEN蛋白该特异位点磷酸化失活的影响及该失活方式调控PI3K/Akt通路在胃癌形成、生长及转移中的作用及机制，进一步探讨胃癌的发生、发展机制，为胃癌基因诊断和治疗提供新的理论依据。

PTEN, an important tumor suppressor gene, has received a lot of attention on its inactivation mechanism in gastric cancer. In the series of our previous studies, we found a new mechanism of PTEN inactivation in gastric cancer, that was phosphorylation inactivation at its Ser380/Thr382/383 sites. The phosphorylation of these specific sites is usually induced by CK2, which will lead to a loss of phosphatase activities of PTEN and the disability in inhibition of PI3K/Akt signaling pathway, thereby results in the increase of tumor susceptibility. Besides, activation of CK2 and PI3K/Akt signaling pathway is often found in gastric carcinogenesis. Accordingly, we hypothesize that CK2 may allow PTEN phosphorylation inactivation at specific sites in gastric carcinogenesis, then will cause activation of the PI3K/Akt signaling pathway and leave abnormal cell biology, which can be involved in gastric carcinogenesis and development. Therefore, this project intends to explore thoroughly the impact of CK2 on phosphorylation inactivation of PTEN at specific sites and how the inactivation manner regulates PI3K/Akt signaling pathway to show its role and mechanism in the formation, development and metastasis of gastric cancer at the whole, cellular, and molecular level through the establishment of the gastric cancer cell model and nude mouse model with PTEN phosphorylation inactivation at specific sites. It will help expound the mechanism in oncogenesis and development of gastric cancer. Furthermore, it will contribute to providing a new theoretical basis for gene diagnosis and treatment of gastric cancer.