炎症因子调控ABC膜转运蛋白介导的NK/T细胞淋巴瘤多药耐药的研究

Extranodal NK/T-cell lymphoma (NKTCL) is a highly aggressive disease and shows a predilection for Chinese. Chemotherapy is the major treatment for NKTCL, however, the patients are often refractory to current treatment and have poor clinical outcome. Our previous high-throughput sequencing results demonstrated that ATP-binding cassette (ABC) membrane transporters are involved in the development of multi-drug resistance in NKTCL. Also, we found that some inflammatory cytokines (IL-6，IL-13 and TNF-α) may function as an important modifier of chemotherapy response in NKTCL. Moreover, these inflammatory cytokines could regulate the expression of ABC membrane transporters at both mRNA and protein levels. We therefore hypothesize that inflammatory cytokines (IL-6，IL-13 and TNF-α) could modulate multi-drug resistance in NKTCL by targeting ABC transporters. To this end, mechanistic and functional studies will be performed to illustrate the role of inflammatory cytokines in the development of multi-drug resistance in NKTCL. Furthermore, we’ll assess the feasibility of inflammatory cytokines as a novel therapeutic target for reversing multi-drug resistance of NKTCL. This study is established on our previous original findings. A better understanding of the role of inflammatory cytokines in the multi-drug resistance may thus pave the way for novel and powerful anticancer therapeutics for reversing multi-drug resistant of NKTCL, and which is of great significance in both theoretical researches and clinical application.

NK/T细胞淋巴瘤(NKTCL)具有高度侵袭性、病程进展快、预后差等特点。化疗是治疗NKTCL的主要手段，然而，多药耐药的产生使大部分患者短期内复发，严重影响疗效及预后。迄今多药耐药产生的机制仍不明确。我们前期研究发现：在NKTCL中，炎症因子IL-13表达明显上升、IL-6和TNF-α表达明显下降，并且其异常表达与化疗疗效相关；这提示以上炎症因子可能参与了NKTCL多药耐药的产生，然而其具体机制尚不清楚。进一步研究表明，以上炎症因子可影响多药耐药相关的ABC膜转运蛋白的表达。因此我们推测：IL-6、IL-13和TNF-a可能通过调控ABC膜转运蛋白的表达介导NKTCL多药耐药的产生。为了验证以上假说，本课题拟从细胞和整体水平明确炎症因子调控ABC膜转运蛋白参与NKTCL多药耐药的作用，并对其分子机制进行深入探索。本项目有望为逆转NKTCL多药耐药提供新的潜在靶点，具有重要的临床意义。

NK/T细胞淋巴瘤(NKTCL)是一种中国高发的淋巴瘤亚型，具有高度侵袭性，病程进展快、预后差等特点。化疗失败的主要原因是原发和继发耐药，特别是多药耐药的产生。迄今多药耐药产生的机制仍知之甚少。我们的预实验发现：在NKTCL中，IL-6基因和ABC家族基因存在高频突变、IL-13表达明显上升、IL-6和TNF-α表达明显下降、ABCC5基因表达明显增加，并且这些表达的改变与化疗疗效相关联。前期我们推测：IL-6、IL-13和TNF-a等炎症因子可能通过NF-κB或STAT途径调控ABC膜转运蛋白从而影响NKTCL多药耐药的产生。为了验证这一假说，本课题从分子、细胞、组织以及动物整体水平系统研究了炎症因子通过调控ABC膜转运蛋白参与NKTCL多药耐药的作用，并对其分子机制进行深入探索。最终发现：炎症因子可能通过NF-κB或STAT途径调控ABC膜转运蛋白从而影响NKTCL多药耐药的产生。本研究有望为逆转NKTCL多药耐药提供新的潜在靶点，为治疗NKTCL提供新的思路。