FOXP1在鼻咽上皮"炎-癌"演进过程中的作用机制研究

The human nasopharynx is directly exposed to the environment, making it vulnerable to numerous environmental carcinogens, including Epstein-Barr virus (EBV) and other pathogens. It has been convincingly shown that chronic non-resolving inflammation caused by environmental pathogens and other carcinogens plays an important role in malignant transformations of the nasopharyngeal epithelium (NPE). Recently, we found that several microRNAs encoded by EBV can directly down-regulate the expression of FOXP1, a candidate tumor suppressor gene located on the short arm of chromosome 3. However, to date, there have been no reports of a mechanistic link between the FOXP1 gene and nasopharyngeal carcinoma (NPC) tumorigenesis. Based on preliminary data and literature searches, we hypothesize that FOXP1 is involved in the non-resolving inflammatory response of the nasopharynx, and ultimately, with the induction of NPC carcinogenesis. In the proposed project, we intend to focus on FOXP1 - the major node in the interaction network between environmental pathogens, the NPE and tumor-associated macrophages (TAMs) - to thoroughly investigate the effects of FOXP1 down-regulation on the NPE and TAMs in the inflammatory microenvironment. We also aim to elucidate the molecular mechanisms controlling the transition from an inflamed NPE to malignant NPC cells. Achieving the goals in this proposal will open new fields in the etiology and pathogenesis of NPC and provide new targets for the early diagnosis and prevention of this cancer.

人鼻咽上皮与外界直接相通，极易受到环境致癌物，包括EB病毒及其它致癌微生物的侵袭。致癌微生物等引起的慢性非可控性炎症可能是导致鼻咽上皮恶性转化的重要原因。我们最近证实EB病毒可通过其编码的microRNAs下调FOXP1基因的表达，FOXP1基因位于3号染色体短臂抑瘤基因富集区，该基因在鼻咽癌发生发展过程中的作用还没有相关报道。我们根据初步实验结果及已有文献推测FOXP1可能参与了鼻咽部的非可控性炎症反应，并最终诱发鼻咽癌。本项目将以FOXP1为关键节点，研究FOXP1表达下调对鼻咽上皮及炎性微环境中肿瘤相关巨噬细胞的影响，从致癌微生物、鼻咽上皮、炎性微环境及它们之间相互作用的角度，探讨鼻咽上皮"炎-癌"演进过程中的分子机制，为鼻咽癌发病机理研究开辟新的方向，并为鼻咽癌早期干预和早期诊断提供新的靶点。

慢性炎症是肿瘤发生发展的重要影响因素。慢性炎症组织中的不断破坏和修复，最终导致了持续存在的非可控性细胞增殖。目前研究认为肿瘤微环境中的炎症细胞在细胞恶性转化中的作用及炎症细胞与肿瘤细胞间的交互作用是非可控性炎症相关肿瘤研究领域的关键问题。炎症细胞是肿瘤间质的重要组成部分，许多炎性细胞，包括肿瘤相关巨噬细胞 (Tumor-Associated Macrophages，TAMs)，在鼻咽癌和胃癌等上皮肿瘤组织中浸润，并促进肿瘤进展。.EB病毒 (Epstein-Barr virus，EBV) 是一人类疱疹DNA病毒，其潜伏感染与一些恶性肿瘤如鼻咽癌、胃癌和许多类型的B细胞淋巴瘤紧密相关。EBV可编码44个成熟miRNAs，分成BHRF1 (BamHI fragment H rightward open reading frame 1) 和BARTs (BamH I-A rightward transcripts) 两簇。已有研究报道一些BARTs簇miRNAs分子在胃癌、淋巴瘤或鼻咽癌中的表达上调且能促进多种肿瘤恶性表型，包括细胞凋亡和周期调控以及肿瘤代谢等， EBV miRNAs可能在EBV介导的肿瘤发生和进展中发挥多种重要的调节功能。但是仍有许多EBV编码的miRNAs在肿瘤发生发展中的作用还不是很明确。 .我们揭示了EBV-miR-BART11通过直接抑制FOXP1表达和激活NF-κB，对炎性微环境的形成维持和炎症诱导的EBV相关上皮肿瘤发生发挥着重要作用。这些数据支持EBV-miR-BART11和FOXP1可以作为EBV相关肿瘤的诊断或者预后的潜在标志物，以及肿瘤免疫治疗的重要靶点。