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

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.

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。

尽管免疫治疗及靶向治疗的进展已显著改善了B细胞淋巴瘤（B-NHL）的预后，但仍有约1/3的患者因难治复发而预后很差。基于分子的新型靶向药物开发为B-NHL整体预后的改善提供了新的机遇。本项目开展了Hippo/YAP信号参与B-NHL发展的分子机制研究及作为潜在的治疗靶点的可行性研究，为B-NHL的新型靶向治疗提供实验基础和理论依据。.主要研究内容包括靶向阻断YAP表达在弥漫大B细胞淋巴瘤（DLBCL）中的抗肿瘤作用，IGF-1R作为上游因子对Hippo/YAP信号通路的调控机制及新型组蛋白去乙酰化酶抑制剂（HDACIs） OSS_128167在B-NHL中的抗肿瘤作用及其机制。.研究结果显示靶向阻断YAP表达可显著抑制DLBCL细胞增殖，诱导细胞凋亡及周期阻滞，增强化疗敏感性，并在体内发挥显著的抗肿瘤效应。IGF-1R抑制剂可抑制DLBCL细胞增殖及小鼠肿瘤生长；靶向抑制IGF-1R可显著下调YAP表达水平，并影响YAP蛋白的亚细胞表达，反之，IGF-1可通过激活IGF-1R诱导DLBCL中YAP的表达。新型HDACIs OSS_128167在体外及体内均发挥了显著的抗DLBCL效应，该作用可能是通过调控Sirt6表达进而抑制PI3K/Akt/mTOR信号通路的活性实现的。.本项目探究了YAP在B-NHL中的表达情况及其作为B-NHL预后生物标记物及抗肿瘤治疗分子靶点的可能性；阐明了Hippo/YAP信号通路参与DLBCL发生发展的上下游调控机制，发现IGF-1R可作为Hippo/YAP通路的上游分子调控DLBCL发展；揭示了HDACIs OSS_128167在淋巴瘤中具有显著的抗肿瘤效应。研究结果揭示了YAP、IGF-1R及Sirt6作为DLBCL治疗靶标的可行性，为NHL的分子靶向治疗提供了新的治疗靶点。