慢性应激通过HPV-YAP1-IGFBP2在宫颈癌失巢凋亡中的作用及机制研究

流行病学研究表明慢性应激等社会心理因素与肿瘤患者的预后关系密切，慢性应激在宫颈癌发生发展中的作用日益受到关注，但相关作用机制的研究仍少有报道。申请人所在MD Anderson的合作实验室近10年来在慢性应激领域开展了深入研究，建立了成熟的束缚应激小鼠模型，并通过应激相关激素处理后反相蛋白阵列（RPPA）分析，筛选出了慢性应激在宫颈癌中的蛋白表达谱。基于前期坚实的研究基础和理论依据，提出以下科学假设：慢性应激通过活化YAP1，并直接靶向于IGFBP2，诱导宫颈癌细胞失巢凋亡抵抗，促进宫颈癌转移和进展。项目拟以慢性心理社会应激在宫颈癌进展转移中的作用为切入点，解析ADRB2-cAMP-PKA经典通路和HPV为主导的全新“慢性应激-HPV-YAP1活化”的作用通路，旨在阐明慢性应激等心理社会因素在宫颈癌进展中的关键机制，为宫颈癌治疗提供新的靶点，并为改进宫颈癌现行的治疗模式提供科学依据。

A substantial number of epidemiological studies have established an important role for biobehavioral stress factors in cancer progression; however, the molecular pathways involved in stress and cervical cancer progression are not well understood. Studies on chronic stress have been well studied during the recent 10 years in the collaboration lab in MD Anderson. We established a preclinical orthotopic mouse model of cervical cancer and used the model to show that daily restraint stress increased tumor growth and metastatic tumor burden. Based on the previous solid experiment data and theories, we supposed that chronic stress induced anoikis resistance by YAP1 activation and targeting IGFBP2 in cervical cancer. It will provide a pivotal molecular pathway for disrupting pro-tumor neuroendocrine signaling in cervical cancer by classical ADRB2-cAMP-PKA and novel “chronic stress-HPV- YAP1” pathways. Collectively, our study aims to determine the key mechanism of psychosocial factors and provide scientific basis for improving the current treatment mode of cervical cancer.