HDAC抑制剂介导Hippo-YAP信号通路在B细胞非霍奇金淋巴瘤发生发展中的作用机制

尽管靶向药物及免疫治疗改善了B细胞淋巴瘤(B-NHL)的预后，但仍有约1/3的患者难治复发。Hippo-YAP通路主要通过影响细胞的增殖和凋亡参与肿瘤发生发展。组蛋白去乙酰化酶(HDAC)抑制剂治疗B-NHL疗效及机制不甚清。我们前期实验发现Hippo-YAP通路关键分子在B-NHL中差异表达，HDAC抑制剂抑制B-NHL增殖并诱导其凋亡，但确切机制尚待明确。为阐明B-NHL中HDAC抑制剂对Hippo-YAP通路的作用机制，本研究拟分析B-NHL中Hippo-YAP通路的活化水平及对B-NHL的影响；探讨HDAC抑制剂对Hippo-YAP的调控机制及联合YAP抑制剂的抗肿瘤效应；动物体内验证HADC抑制剂对Hippo-YAP通路的作用机制。目的为阐明Hippo-YAP通路在B-NHL发生发展中的作用，揭示HDAC抑制剂新的作用机制及联合用药策略，为改善B-NHL的预后提供理论和实验依据。

B-cell non-Hodgkin lymphoma (B-NHL) is the most common subtype of NHL. Although targeted drugs and immunotherapy have significantly improved the prognosis of B-NHL patients, there still approximately 1/3 of them presented refractory or recurrent process. Hippo-YAP pathway is a novel signaling cascade recently found to play a tumor suppressor role in tumorigenesis. This pathway involved in the initiation, invasion and drug resistance by interfering the proliferation and apoptosis of tumor cells. Histone deacetylase (HDAC) inhibitors revealed unsatisfying efficacy in treatment of B-NHL. Our previous studies have demonstrated aberrant activation of Hippo-YAP signaling in the tissues and cell lines of B-NHL. HDAC inhibitors exhibited anti-proliferative and pro-apoptotic effect in B-NHL cells. To further explore the function of Hippo-YAP signaling and the regulatory effect by HDAC inhibitors, we aim to deeply investigate the activation of Hippo-YAP signaling and its correlation with prognosis in B-NHL, detect the function of Hippo-YAP signaling on cell survival and autophagy, explore the regulatory mechanisms of HDAC inhibitors on Hippo-YAP signaling, and verify the above mechanisms in vivo. This study will demonstrate an important role of Hippo-YAP pathway in the development and progression of B-NHL, and identify the novel mechanism and combination strategy of HDAC inhibitors. The finding of this study will provide novel theoretical basis to improve the prognosis of B-NHL.