小干扰素诱导膜蛋白IFITM3在微环境JAK/STAT信号通路中对胶质瘤侵袭性生长的调控机制

Glioma,one of the most common neoplasms in human brain, is always a hotspot of neurosurgery because of its invasion. The treatment for malignant glioma which is used in clincal practice at present has its limition on increasing the survival pririod of patients. Basic research for the mechanism of glioma can provide us a new insight on this lethal disease. Theoretically, molecules which are upregulated specifically during matastasis of tumor can be regarded as a potential theroputic target for malignant glioma. During our previous work of identification of molecules involved in tumor microenvironment and metastasis, we demonstrated that IFITM3 (Interferon induced transmembrane protein 3) is upregulated during invasion of glioma, suggesting that IFITM3 may be a critical regulator of invasion. Our purpose is to elucidate the role of IFITM3 in JAK/STAT Signaling Pathway of tumor microenvironment in the invasive growth of malignant glioma and its downsteam signaling pathway. We plan to evaluate the potential application of ITIM3 as a theraputic target for glioma by elucidating the relationship between IFITM3 and the invasion of glioma by in vitro and in vivo.

胶质瘤一直是神经外科研究的热点和难点。传统的综合治疗在延长胶质瘤病人生存期方面似乎达到了“极限”。新的治疗方案必须向基础寻求答案。理论上讲，肿瘤侵润生长中特异性活性上调的信号转导通路的任何关键分子，都可能成为潜在的恶性胶质瘤治疗的分子靶点。申请者长期关注肿瘤微环境及胶质瘤侵润生长相关分子，通过研究发现IFITM3（Interferon induced transmembrane protein 3）在胶质瘤侵袭性生长过程中异常上调，所以IFITM3可能是胶质瘤侵袭性生长中的核心分子。本研究拟阐明IFITM3在微环境JAK/STAT信号通路中对胶质瘤的恶性表型尤其是高度侵袭生长的影响，深入探讨其可能的分子机制。目前在于鉴定IFITM3在体外和体内IFITM3与胶质瘤侵袭性生长的关系，明确其功能和机制，提供有助于临床肿瘤治疗的分子靶点，评价IFITM3作为胶质瘤靶向治疗分子的应用价值。

胶质瘤恶性程度高、预后差，多以侵袭性生长为主，是目前神经外科临床的重要挑战。申请者研究发现IFITM3通过激活STAT3促进在TGF-β介导的胶质细胞增殖及浸润生长中起到重要作用。同时，发现miR-141靶向调控Hotair及其靶基因进而调控胶质瘤细胞的恶性增殖和侵袭性生长。LncRNA RNA-SPRY4-IT1通过上调SKA2促进胶质瘤细胞增殖和侵袭性生长。此外，长链非编码RNA-ATB激活星形胶质细胞促进胶质瘤细胞浸润生长。从多角度阐明，在胶质瘤微环境中，IFITM3及深入研究发现的部分非编码RNA 对胶质瘤恶性表型的影响及其调控机制。本研究对进一步揭示胶质瘤发病的分子机制、个体化治疗新靶点提供理论依据。