HIF-1α调控CXCR4在弥漫大B细胞淋巴瘤侵袭与进展中的作用及机制研究

Hypoxia-HIF-1α-CXCR4 axis plays an important role in the invasion and progression of malignant biological behavior in diffuse large B cell lymphoma (DLBCL). To illustrate the mechanism in depth, this study will: 1) To confirm that the specific silencing or overexpression of HIF-1 and CXCR4 may promote the proliferation and invasion of DLBCL cells in an in vitro model of hypoxia; 2) To prove that HIF-1αbinds directly to the functional HRE1 site of CXCR4 gene promoter and activates the transcription of CXCR4, thus regulating the expression of CXCR4 and promoting the invasion and progression of DLBCL; 3) To verify that that CXCR4 can further promote the invasion and progression of DLBCL through the PI3K/AKT/mTOR pathway;4)To prove that the targeted inhibition of HIF-1αand CXCR4 can inhibit the growth and invasion of DLBCL transplanted tumors. We hope to find out the role of HIF-1 regulatory CXCR4 in the invasion and progression of DLBCL through this study, to provide theoretical basis for the development of the HIF-1α-CXCR4 axis as the target point for the treatment of DLBCL / combined therapy, and to provide a new direction for the further improvement of the therapeutic effect of DLBCL.

缺氧-HIF-1α-CXCR4R轴在弥漫大B细胞淋巴瘤（DLBCL）侵袭和进展恶性生物学行为中发挥了重要作用。本课题拟在前期工作的基础上：1）在体外缺氧模型中证明特异性沉默或过表达HIF-1α和CXCR4可促进DLBCL细胞增殖和侵袭；2）证明HIF-1α通过直接与 CXCR4 基因启动子的功能性 HRE1 位点结合，激活 CXCR4 的转录，从而调控CXCR4表达，促进DLBCL的侵袭与进展；3）证明CXCR4可通过PI3K/AKT/mTOR通路进一步促进DLBCL的侵袭与进展；4）在动物模型中证明靶向抑制HIF-1α和CXCR4可抑制DLBCL移植瘤的生长和侵袭。我们希望通过本研究，明确HIF-1α调控CXCR4在DLBCL侵袭与进展中的作用机制，为开展以HIF-1α-CXCR4轴为靶点治疗/联合治疗DLBCL的临床方案提供理论基础，为改善DLBCL的预后提供新的方向。

本课题阐明了缺氧条件下HIF-1α及CXCR4在DLBCL侵袭进展中的作用及机制；证明CXCR4是HIF-1α的直接靶基因，并通过激活PI3K/AKT/mTOR通路，导致HIF-1α的表达增高，进一步促进DLBCL的侵袭与进展；同时在临床标本中验证HIF1α和CXCR4在DLBCL侵袭进展过程中的作用，并在体外模型中验证新型HIF-1α抑制剂KC7F2和CXCR4抑制剂WZ811的抗淋巴瘤作用。本课题的研究结果可以为DLBCL侵袭进展的早期诊断、基因靶向治疗以及临床预后提供新的思路，同时为开展以HIF1α-CXCR4轴为靶点治疗/联合治疗DLBCL的临床方案提供理论基础，为改善DLBCL的预后提供新的方向。