鼻咽癌患者高密度脂蛋白（HDL）组分重塑及其促进肿瘤转移的作用与机制

Our previous data have shown that serum HDL-C level predicted distant metastasis and poor prognosis in patients with nasopharyngeal carcinoma (NPC). Human isolated HDL could promote proliferative and invasive ability of nasopharyngeal carcinoma cells in vitro and its effects could be reduced by SR-BI knock down. Furthermore, the levels of SAA in HDL isolated from patients with NPC were significantly higher than those in healthy. Taken together, we suppose that HDL could directly promote proliferative and invasive ability of NPC cells by combined with SR-B1 receptor. It also could promote the tumor progression by pro-inflammatory cytokines secreted in inflammatory cells activated by SAA, which was up-regulated in NPC patients due to HDL remodeling. To verify it, we will first perform a large multicenter epidemiologic study to determine the interrelationship between serum HDL level, expression of SR-BI and the clinical features of patients with NPC. Next we will further investigate the mechanism of the effects of HDL on NPC cells through HDL-SR-BI pathway. And then, we will observe the significance and mechanism of SAA in HDL remolding of patients with NPC, which could lead to metastasis. In addition, proteomic analysis will be performed to screen and verify the possible factors which might be related with HDL remodeling. The above studies will provide the new sight for investigating the mechanisms of metastasis in NPC.

课题组前期研究发现鼻咽癌患者外周血HDL-C的水平与肿瘤转移和患者的预后不良密切相关，分离纯化的HDL可促进鼻咽癌细胞的增殖和侵袭，而沉默HDL受体SR-BI可以降低HDL对肿瘤细胞的作用。进一步研究表明，鼻咽癌患者分离的HDL中SAA的水平显著高于健康者。我们推测，HDL一方面通过其受体SR-BI直接促进肿瘤细胞增殖及侵袭能力；另一方面，患者HDL组份重塑而至SAA含量升高，SAA又可通过激活炎症细胞而最终促进肿瘤进展。为此，本项目拟首先通过大样本、多中心资料阐述鼻咽癌患者血HDL水平与临床病理特征的关系；继而检测鼻咽癌组织中SR-BI的表达及其临床意义，并深入探讨HDL通过SR-BI促进肿瘤进展的机制；同时观察SAA在鼻咽癌患者HDL组份重塑的临床意义及促进肿瘤转移的作用和机制；最后利用蛋白组学进一步筛选可能与HDL组份重塑相关的因子并验证；从而为鼻咽癌转移机理的研究提供新的思路。

鼻咽癌鼻咽癌是好发于我国华南地区的恶性肿瘤，发病原因可能与EBV感染、遗传及环境因素、生活习惯，抽烟等习惯密切相关。本研究的目的即探讨血脂及脂蛋白HDL与鼻咽癌患者预后的关系，并研究脂蛋白在鼻咽癌细胞中体外的生物学效应。研究纳入了2443例来自三个独立研究中心的初治无转移的鼻咽癌病人。研究治疗HDL-C的水平与患者预后的价值。应用COX 风险模型及log-rank方法分析血浆中HDL-C与总生存OS的关系。并研究HDL对鼻咽癌细胞增殖、克隆、凋亡的生物学效应。结果显示：HDL-C高的患者预后（总生存时间、无进展生存时间和无远处转移生存时间）显著差于HDL-C低的患者. 同样的，亚组分析III-IV期鼻咽癌病人，治疗前高水平HDL-C的病人其总生存OS时间缩短(P<0.01)。多因素分析得出HDL-C在训练组可作为独立的预后因素(P<0.01).。在验证组中，HDL-C同样可作为独立的预后因素。体外实验证明HDL可通过其受体SR-B1增强鼻咽癌细胞的增殖、克隆形成、体外侵袭并降低化疗敏感性；另外，HDL可能通过与受体SR-B1结合激活其下游信号通路，进而促进鼻咽癌细胞的增殖、克隆形成及迁移和侵袭，最终影响了鼻咽癌患者的预后。结论：治疗前HDL-C水平可作为鼻咽癌患者的预后不佳的标志物。其主要是通过增强细胞增殖、克隆形成能力，转移能力及降低化疗敏感性发挥生物学效应。