干扰素诱导基因C19orf18在淋巴细胞迁移的调控机制研究

There are up to 2000 genes which can be induced by interferon so far, however, both their function and molecular mechanism are poorly understood for most of them. Here, on the basis of the microarray data on super compound interferon treated cells, we confirmed a novel gene C19orf18 which is not reported before and can be actively induced by type I interferon. C19orf18 is evolutionally conserved from mouse to human species. It was observed that C19orf18 mainly locates in the cellular cytoplasm but not nucleus with higher expression level in the hemopoietic cells; GEO profiles database showed that C19orf18 expression in peripheral blood mononuclear cells from leukemia patients was significantly higher than that of health control, this data was very similar to that of mouse leukemia model with elevated C19orf18 expression level in bone marrow compared to the health group. Over expression of C19orf18 and knockdown of this gene demonstrated it has no effect on cell growth but plays a vital role in driving cell migration. In this study, C19orf18-KO mice were constructed, we want to further confirm this protein's physiological function and study its molecular mechanism through both in vitro lymphocyte cell migration assays and its effect on the tumor growth in vivo by mouse tumor transplantable models respectively.

目前干扰素诱导蛋白高达2000多个，许多蛋白功能和分子机制并不清楚。本项目以干扰素刺激芯片数据为切入点，发现一个新型干扰素诱导基因C19orf18, 其功能目前无任何报道，前期研究结果表明：该分子进化保守，受干扰素刺激表达，蛋白主要定位于细胞质，而不在细胞核中；在造血系统来源的组织表达量较高，GEO数据显示C19orf18在白血病人外周血中的表达水平显著高于正常对照组，同时小鼠白血病模型中在骨髓中的表达量也高于健康组。过表达和敲低C19orf18实验表明它不影响生长，但显著促进细胞迁移。本项目中，基于自主构建的C19orf18敲除小鼠，开展小鼠原代免疫细胞体外迁移实验和肿瘤移植模型分别进一步证实C19orf18在体内调节淋巴免疫细胞迁移的生物学功能，并研究其影响肿瘤生长病理过程相关的分子机制。

目前干扰素诱导蛋白高达2000多个，许多蛋白功能和分子机制并不清楚。本项目以干扰素刺激芯片数据为切入点，发现一个新型干扰素诱导基因C19orf18, 其功能目前无任何报道。本项目研究表明C19orf18参与病毒感染应激反应，是一个I型干扰素下游诱导基因，结构信息学预测C19orf18从小鼠到人进化保守，为单次跨膜蛋白，其蛋白主要定位于细胞质，可通过蛋白酶体途径进行蛋白降解，C19orf18不影响细胞的生长，过表达人源C19orf18可以显著促进Hela, A549的迁移，敲低其表达抑制Raji细胞的迁移；但基因敲除的鼠源C19orf18可以显著促进小鼠原代真皮成纤维细胞的迁移能力而不影响脾脏淋巴细胞的迁移能力。对基因敲除C19orf18小鼠进行肿瘤移植肿瘤模型结果表明，相对C19orf18野生型，小鼠C19orf18敲除后可影响淋巴细胞在肿瘤组织浸润减少和MDSC细胞肿瘤浸润增多进而促进肿瘤生长。在个人生殖发育上，C19orf18基因敲除并不影响小鼠个体生长和成年小鼠精子活力，但C19orf18基因敲除显著推迟小鼠精子早期发生过程。该基因研究属于原创研究工作，该研究的基础成果将为进一步理解细胞迁移及肿瘤生长病理相关分子机制以及干扰素诱导下游分子的相关机制提供重要的科学参考基础

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