结直肠癌中Annexin A4的SUMO化修饰 促其膜浆转位并参与细胞上皮-间质转化的机制研究

Annexin A4(ANXA4)是钙依赖磷脂结合蛋白，被报道在多种肿瘤中表达上调、可促进肿瘤侵袭转移。我们前期研究发现ANXA4在结直肠癌(colorectal cancer CRC)中表达上调并存在由细胞膜转位至细胞浆的现象；其表达异常可影响CRC上皮-间质转化(epithelial- mesenchymal transition，EMT)及侵袭转移能力，但其具体机制尚不清楚。已有研究证实SUMO化修饰可调控ANXA家族分子表达，影响蛋白质亚细胞定位。但ANXA4的SUMO化修饰以及对蛋白质膜浆转位的影响尚无人问津。我们利用生物信息软件预测到ANXA4存在SUMO化修饰位点，且初步研究发现ANXA4主要被SUMO2/3修饰。我们提出在CRC中ANXA4的SUMO化修饰可导致其膜浆转位并参与EMT的发生。通过该研究，不但可以丰富结直肠癌发生发展机理，而且可为其诊断和治疗提供靶点。

Annexin A4 (ANXA4), a Ca2+ regulated phospholipid-binding protein, is reported to exhibit high expression in a variety of tumors and may promote the invasion and metastasis of them. Our previous studies showed that compared with normal colorectal epithelium，ANXA4 was high expressed and translocated from cell membrane to cytoplasm in CRC. And the elevated expresion of ANXA4 can affect the pithelial-mesenchymal transition (EMT) and its invasive and metastatic capability. But the concrete mechanism remains unclear. Some researches confirmed that the molecular expression of Annexin A family can be regulated by SUMO modification (SUMOylation) and the SUMOylation was revealed to mediate subcellular distribution of proteins. However, the SUMOylation of ANXA4 and its work on the delocation from cells membrane to plasma is still unknown. We predicated potential SUMOylation sites of ANXA4 by means of bioinformatics software, and the preliminary study found ANXA4 was mainly modified by SUMO2/3. We hypothesized that SUMOylation delocalizes ANXA4 from cells membrane to cytoplasm and is involved in Epithelial-Mesenchymal Transition (EMT) in CRC. Our data will not only enrich the mechanism of initiation and development, but also provide targets of diagnosis and treatment for colorectal cancer.