趋化因子轴MIG/CXCR3在套细胞淋巴瘤中的功能及其作用机制

Interactions between chemokines and their receptors have reported to be involved in the growth, proliferation, migration and drug resistance of tumor cells. The role of monokine induced by interferon gamma (MIG) and its receptor, CXCR3, in mantle cell lymphoma (MCL) is still unknown. Normal B cells don’t express CXCR3, and malignant B cells specifically express CXCR3, while the levels of expression in B-cell lymphomas are heterogeneous. We previously found that the MIG and CXCR3 in peripheral blood serum and bone marrow, respectively, were up-regulating expressed in newly diagnosed MCL patients. Therefore we speculate that MIG/CXCR3 may promote MCL cells to survive, migrate and also be involved in chemotherapy resistance mediated by lymphoma microenvironment. In this study we will analyze the expression of MIG/CXCR3 in serum and bone marrow of patients before and after chemotherapy. Then we will study the biological characteristics in MCL cells by MIG secretion, and the interactions between MCL cells and stromal cells in lymphoma microenvironment at the cell level in vitro. We will further explore the molecular mechanism of MIG/CXCR3 actions in MCL. In the end we will evaluate the potent anti-tumor activity of CXCR3 antagonist in a xenograft model of human MCL in vivo. This study will establish a theoretical basis for targeted therapy of chemokine receptors and provide a new strategy for MCL diagnosis and treatment.

趋化因子及其受体的相互作用参与肿瘤细胞生长、增殖、转移以及耐药发生。MIG（γ干扰素诱导单核因子）及其受体CXCR3在套细胞淋巴瘤（MCL）中的具体功能尚不清楚。正常B细胞不表达CXCR3，肿瘤性B细胞特异性表达CXCR3，其表达水平因疾病类型而不同。我们前期研究发现趋化因子轴MIG/CXCR3在初诊MCL患者血清和骨髓中表达显著上调，因此推测MIG/CXCR3能促进MCL细胞存活、迁移，并参与淋巴瘤微环境介导的化疗耐药。本项目拟分析MIG/CXCR3在化疗前后MCL患者骨髓和外周血的表达水平变化，从体外细胞水平研究MIG如何调控MCL细胞生物学特性以及肿瘤细胞与淋巴瘤微环境中基质细胞之间的相互作用，深入探讨其发挥作用的分子机制，从体内水平评价CXCR3拮抗剂在MCL移植瘤动物模型中的抗肿瘤作用。本项目的顺利开展为针对趋化因子受体的靶向治疗提供理论依据，为MCL诊疗提供新思路和新策略。

套细胞淋巴瘤（MCL）是非霍奇金淋巴瘤的独特亚型，具有高度侵袭性和临床异质性的特点，超过90%的MCL患者起病时即有骨髓、消化道或者外周血结外浸润的表现。由于MCL具有易复发、进展快和预后差等特点，且目前尚无针对其有效治疗的靶向药物，故迫切需要新的药物和治疗策略。肿瘤微环境为肿瘤细胞存活和增殖提供了关键场所，是肿瘤细胞赖以生存和进展的土壤。恶性淋巴瘤迁移和归巢受肿瘤细胞表面的趋化因子受体和淋巴瘤微环境中基质细胞分泌的趋化因子相互作用的共同调控。趋化因子轴MIG/CXCR3在MCL中的表达及其作用未见有相关研究报道。本项目研究趋化因子受体CXCR3在初诊MCL患者骨髓、外周血和淋巴结等组织中的表达水平，检测治疗前后血清MIG水平的变化，分析其与临床重要特征、疗效和预后因素的相关性，发现MCL患者送检肿瘤标本均不同程度表达CXCR3，淋巴结和脾组织中的表达水平明显高于骨髓和外周血，且CXCR3表达水平与肿瘤负荷、早期转移和预后密切相关；经诱导治疗后MCL患者血清MIG水平明显降低，其变化水平与循环肿瘤细胞数目和微小残留病呈显著正相关，血清MIG升高组患者无进展生存时间和总生存时间均显著短于血清MIG降低组患者，这些结果表明血清MIG水平可以作为评价MCL疾病进展和预后不良的有效指标之一。我们进一步探讨趋化因子轴MIG/CXCR3对MCL细胞增殖、凋亡和侵袭中的作用其发挥作用的分子机制，发现CXCR3促进MCL细胞系Jeko-1增殖，抑制Jeko-1细胞凋亡；添加CXCR3拮抗剂AMG487则显著抑制Jeko-1细胞增殖，诱导Jeko-1细胞凋亡；此外，MIG以浓度依赖的方式上调了PI3K和AKT总蛋白水平以及磷酸化水平，从体外水平证实PI3K/AKT信号通路可能是MIG/CXCR3对MCL细胞发挥作用的机制之一。总之，趋化因子轴MIG/CXCR3在MCL发生、增殖和转移中发挥着重要作用，为针对趋化因子受体靶向MCL的治疗提供了重要的理论依据。