天然免疫分子乳铁蛋白抑制鼻咽癌的发生发展

鼻咽癌是一种多基因遗传性肿瘤，其发病与遗传因素和环境因素密切相关，基因与环境因素间存在复杂的交互作用. 本课题组通过全基因组杂合性丢失扫描及比较基因组杂交，发现鼻咽癌中3号染色体短臂存在高频缺失，通过鼻咽癌家系连锁分析，发现染色体3p21区域为鼻咽癌易感基因区，随后通过表型克隆策略在该染色体区域分离鉴定了鼻咽癌候选易感/抑瘤基因LTF. LTF基因编码的乳铁蛋白是一种广泛分布于哺乳动物乳汁、鼻咽分泌物、泪液等分泌液中的天然免疫分子，在正常鼻咽部高表达而在鼻咽癌组织中表达显著下调，且与鼻咽癌的临床进展及侵袭转移密切相关. 病例-对照关联分析发现LTF基因中2个单核苷酸多态位点与鼻咽癌发病风险密切相关，且多态性改变可影响LTF基因的表达水平. 我们发现乳铁蛋白能与EB病毒在人B细胞表面的受体CD21结合，阻断EB病毒入侵宿主B细胞，并抑制EB病毒由B细胞向鼻咽上皮细胞的传递，在鼻咽上皮的癌变过程中起保护作用. 我们还发现LTF能通过MAPK和AKT等通路抑制鼻咽癌细胞的增殖和侵袭转移. 这些结果表明乳汁中的天然成份乳铁蛋白在鼻咽癌等EB病毒相关疾病的防治中具有重要的应用前景.

Innate Immune Protein Lactotransferrin Prevents Initiation and Arrests Progression of Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is a polygenic inheritance disorder. Both environmental and genetic risk factors play important roles in NPC carcinogenesis and progression, and there are complex interactions between genes and environmental carcinogens. Whole-genome loss of heterozygosity analyses and comparative genomic hybridization analyses identified that the short arm of chromosome 3 were high-frequency deleted in NPC biopsies, and genetic linkage analyses of human NPC families identified chromosome 3p21 as a new susceptibility gene region. Using phenotype cloning strategy, we identified LTF as a tumor suppressor and susceptibility gene of NPC on chromosome 3p21. Lactotransferrin, encoded by LTF gene, is an innate immune protein that widespreadly secreted into most biological fluids including mammal milk, nasal secretions, tears, etc. LTF was highly expressed in normal nasopharynx and significantly down-regulated in NPC tissues and down-regulation of LTF was correlated with progression, invasion and metastasis of NPC. A case-control study implied that two single nucleotide polymorphisms (SNPs) in LTF gene affect the expression level of LTF, and associated with NPC risk. We found that lactotransferrin could protect human primary B lymphocytes and nasopharyngeal epithelial cells from Epstein-Barr virus (EBV) infection by binding to CD21, the EBV receptor on B lymphocyte surface, blocking the infection of EBV into B cells and inhibiting the transfer of EBV from B cells to nasopharyngeal epithelial cells. In addition, lactotransferrin could reduce the EBV stimulated inflammatory responses and protect nasopharyngeal epithelial cells from carcinogenesis. We also found that lactotransferrin could inhibiting the proliferation and metastasis through MAPK and AKT pathways. These results implied that as a natural component of milk, lactotransferrin will has important application potential in the prevention and therapy of NPC and other EBV related diseases.