慢性精神应激活化β2-AR/Cdc42信号通路促进胰腺癌转移的机制研究

Chronic psychological stress is an important risk factor leading to pancreatic cancer initiation and development through sympathetic nervous system. Sympathetic nerve-catecholamine-adrenergic receptor has been documented to play a vital role in chronic stress-induced pancreatic cancer development. Our preliminary data reveal that high expression of β2-adrenergic receptor (β2-AR) predicts worsened prognosis in patients with pancreatic cancer. In addition, β2-AR associates with and activates cell division cycle 42 (Cdc42), a Rho GTPase that plays a central role in the remodeling of cytoskeleton, and enhances cancer cell migration and invasion ability. On the basis of these findings, we put forward the hypothesis that β2-AR may initiate Cdc42-related signaling transduction to drive pancreatic cancer metastasis and invasion. Our project aim to first determine the expression profiles of β2-AR and Cdc42 in pancreatic cancer, and the association between these two proteins and the prognosis of pancreatic cancer patients. Thereafter, we will clarify the association between β2-AR and Cdc42, as well as their influence on Cdc42 downstream pathways, including PAK1 and Par6-aPKC, and analyze the effect of enhancing cell migration and invasion ability. Finally, we will delineate the effect of chronic stress-induced β2-AR/Cdc42 signaling on pancreatic cancer.metastasis using metastatic xenograft model in nude mice. Our research may help clarify the molecular mechanism underlying psychological stress-triggered pancreatic cancer metastasis, and provide novel theoretical basis for the development of target therapy of pancreatic cancer.

慢性的精神压力是胰腺癌发生发展的重要危险因素之一，其可通过交感神经-儿茶酚胺-肾上腺素能受体通路促进胰腺癌的恶性进程。课题组前期研究显示β2肾上腺素能受体（β2-AR）在胰腺癌组织中表达显著升高且与患者的不良预后相关，并且β2-AR可结合并活化细胞骨架调控的关键蛋白Cdc42及促进胰腺癌细胞迁移侵袭。基于此，我们提出β2-AR可通过结合并激活Cdc42进而介导Cdc42下游信号通路的活化，导致胰腺癌转移和侵袭的假说。我们拟首先检测胰腺癌组织中β2-AR和Cdc42表达的相关性及对预后的影响；接着分析两者的相互作用，并研究该作用对下游PAK1和Par6-aPKC等信号通路及胰腺癌细胞迁移侵袭能力的影响；最后在裸鼠胰腺癌体内转移瘤模型中分析精神应激通过β2-AR/Cdc42信号通路对胰腺癌转移的影响。本研究将揭示慢性精神应激促进胰腺癌转移的分子机制，为胰腺癌的临床治疗提供新的实验依据。

近年来大量研究证据表明慢性精神应激与胰腺癌的恶性进程有密切关系，其中β2肾上腺素能受体（β2-AR）发挥重要作用，但具体机制尚未完全阐明。本项目研究发现，胰腺癌细胞表面β2-AR活化后可与细胞内Cdc42发生结合，并进一步激活Cdc42下游信号通路。β2-AR/Cdc42相互作用可增强胰腺癌细胞体外迁移及侵袭能力，拮抗β2-AR或干扰细胞内Cdc42蛋白表达可以显著抑制β2-AR活化引起的胰腺癌细胞移动能力增强。在胰腺癌组织中，β2-AR和Cdc42均为高表达，其表达模式与肿瘤的淋巴结转移情况及临床分期相关。另外，生存分析结果表明β2-AR/Cdc42高表达的胰腺癌患者预后较差。该研究初步明确了β2-AR/Cdc42对胰腺癌恶性进程的影响，并将成为判断胰腺癌预后的指标，以及为其靶向治疗提供新的药物开发靶点。