NRAGE调控DNA损伤同源重组修复及其促进食管癌放化疗抵抗的机制

NRAGE is also known as MAGE-D1 or Dlxin-1, is a key protein regulating cell function. The general consensus is that NRAGE could inhibit the tumor cell proliferation and metastasis and apoptosis. But NRAGE has high expression in many kind of tumor tissues, suggestinga possible role of oncogene, constituting a dilemma of NRAGE function. Our preliminary study showed that the expression of NRAGE in esophageal cancer tissues is 3 times the level of matched adjacent tissues , and the coding protein can interact with DNA damage repair protein Rad51, RNF8 and Bard1, maintaining their protein levels, and promoting the repair of DNA damage. Therefore, we put forward the hypothesis, NRAGE play a double-edged sword function by promoting DNA repair, it maintains the genomic stability in normal cells, preventing the malignant transformation of cells; in tumor cells, it also maintains genomic stability, promoting resistance to chemotherapy. This project will focus on our NRAGE knockout mice to study the function and molecular mechanism of how NRAGE promotes DNA damage repair and resistance of radiotherapy and chemotherapy in esophageal cancer resistance，to provide new ideas for the prevention of tumors resistant.

NRAGE是调控细胞功能的一个重要蛋白。一般认为NRAGE能够抑制肿瘤细胞增殖促进凋亡。但NRAGE在多数肿瘤中存在高表达的现象，表明可能具有原癌基因功能，这一矛盾构成NRAGE功能研究的困境。我们前期研究表明，食管癌组织中NRAGE表达水平是癌旁组织的3倍，该蛋白可以结合DNA损伤重组修复（Homologous recombination repair, HR）的核心蛋白Rad51,RNF8与Bard1，维持蛋白稳定，促进DNA损伤HR修复。因此提出假设，NRAGE通过促进HR修复保护基因组稳定，阻止细胞恶变；但在肿瘤细胞中，这种维持基因组稳定的作用也能够促进肿瘤对放化疗的抵抗。本项目将着重在课题组已有的NRAGE敲除小鼠模型中研究该基因促进DNA损伤重组修复的功能及其分子机制，以及促进食管癌抵抗放化疗的作用，为肿瘤耐药防治提供新的思路。

神经营养因子受体结合黑色素抗原编码基因同源体NRAGE在化疗耐受食管癌细胞核中显著增加，并且促进了食管癌细胞的增殖。但是，NRAGE是否参与DNA损伤应答反应目前尚无报道。本项目研究中，我们发现NRAGE特异性的参与了同源重组损伤修复，体内及体外的研究数据表明其高表达导致食管癌细胞对放化疗的耐受性显著增强。进一步机制研究表明，NRAGE不仅通过泛素蛋白酶体信号调控同源重组损伤修复蛋白RNF8和BARD1的稳定性，还与RNF8-BARD1的RING结构域相互作用形成一个三聚复合物。此外，在食管癌肿瘤样本中，NRAGE的表达与RNF8和BARD1的表达显著相关。因此，我们的研究结果阐述了NRAGE参与DNA损伤修复的新功能，也许在未来5-10年，我们可以通过靶向抑制NRAGE及RNF8-BARD1的表达增加食管癌的抗肿瘤放化疗敏感性。