抗癌蛋白FAM172A2在肝癌生物治疗中的作用机制研究

The incidence rate of liver cancer is high, those patients were short survival, one of the fundamental reasons was lack of effective therapy. The preliminary studies of our group found that the function of FAM172A2 was unknown in PubMed, which encoded proteins significantly inhibit the proliferation of hepatoma cells, so that we hypothesize that it maybe the typical tumor suppressor gene.So far，there were no functional studies of it had been reported. FAM172A2 need to have further studies. The preliminary results of us found the relationship between FAM172A2 and stress of endoplasmic reticulum. We will research the anticancer function of FAM172A2 in vivo and in vitro, and the mechanism associated to UPR signal transduction pathway, cell cycle. The modification mechanism by O-GlcNAc glycosylation and regulation of enzyme (glycosyltransferase enzyme OGT and glycosidase OAT) of it should be studied by animal models and hepatoma cell lines. FAM172A2 protein may be used as a new anti-cancer protein to the biological treatment for liver cancer, and the main purpose of us is to determine the role of FAM172A2 on the treatment for hepatocelluar carcinoma.

肝癌发病率高，生存期短，其根本原因之一是缺乏有效治疗药物。本课题组前期研究了一功能未知基因(FAM172A2)，其编码蛋白显著抑制人肝癌细胞增殖，与内质网应激密切相关，我们推测该基因可能是一个典型的抑癌基因。至今国内外未见其功能研究报道，故本项目属于源头创新。本课题组旨在通过体外细胞模型及裸鼠体内抑瘤实验，探讨FAM172A2抑制肝癌细胞增殖的机制，即涉及的抗肝癌作用的UPR信号转导通路、调控的肝癌细胞周期蛋白，以及通过对O-GlcNAc糖基化修饰调控酶（糖基转移酶OGT和糖苷酶OAT）表达的影响调控细胞内O-GlcNAc糖基化修饰过程；并通过体内抑瘤实验，确定FAM172A2体内抗肝癌作用并探讨可能的最佳体内抑瘤剂量。FAM172A2蛋白可能作为一种新的抗癌蛋白用于肝癌的生物治疗，本课题立项主要目的在于为FAM172A2用于肝癌治疗奠定临床前期研究工作基础。

我们的研究结果表明,FAM172A在肝细胞性肝癌或肝硬化患者的肝组织中其表达明显抑制。本课题阐明FAM172A对肝癌细胞系HepG2细胞功能的调节作用。并且应用共焦激光扫描技术明确了FAM172A蛋白在HepG2细胞的表达定位；应用表面等离子体共振实验确定FAM172A与活性单糖无结合活性，但与Ca2 +离子存在明确的结合活性。FAM172A在HepG2细胞的明确定位于内质网，其蛋白在正常肝组织中存在适度表达而但在肝癌组织中的表达明显降低。HepG2细胞与FAM172A重组蛋白培养后，细胞周期S期受到抑制，在重组蛋白最高的浓度(100 ng / mL)时则被完全抑制。HepG2细胞的增殖可以被FAM172A重组蛋白显著抑制,这一作用机制可能与Notch-3和细胞周期素E的表达上调密切相关。我们的研究结果表明,FAM172A可能是一个新的肿瘤抑制基因,其对肝癌细胞周期控制发挥了重要作用,其对肿瘤细胞增殖的抑制作用机制可能是通过Notch-3信号通路介导G1 / S期捕获所致。