食管鳞癌是我国特有的高发恶性肿瘤，发病率和死亡率均为世界第一。我们首次报道了AJUBA是食管鳞癌的重要突变基因，并以截短突变为主。在青年基金支持下，通过体内和体外实验证实AJUBA表达水平与T分期和分化程度相关，野生型Ajuba具有促进食管鳞癌细胞增殖、迁移、侵袭、耐药、抵抗凋亡的作用。然而，AJUBA基因截短突变的生物学效应仍不明确，对形态学正常的食管、癌前病变的测序研究显示AJUBA基因的截短突变发生于食管恶变的早期。本项目计划构建条件性定点敲入截短突变的细胞和动物模型，研究AJUBA截短突变对食管鳞癌细胞和永生化食管上皮细胞恶性表型的影响及其分子机制；筛选与AJUBA各主要结构域相互作用的分子及其上下游关系，揭示AJUBA参与食管癌前病变恶变进展的分子机制，评价其作为个体化治疗靶点或标志物的价值。

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors in China, with the highest incidence and mortality in the world. Our previous genomic sequencing studies, supported by National Science Fund for Distinguished Young Scholars，demonstrated that the mutation signature of AJUBA in esophageal cancer shared some similarities with that of RB1 ,and the expression level of AJUBA was correlated with T staging and level of differentiation of tumors ,both in vivo and in vitro. Furthermore, we found wild-type AJUBA played an important role in carcinogenesis, tumor progression, proliferation and anti-apoptosis in ESCC. However, it remains controversial over the biological effect of truncated mutation of AJUBA, and our results indicated the gene mutation of AJUBA took place in the early phase of malignancy with the help of gene sequencing. After building conditional knock-in models of short truncated mutation in cell and animal as designed, we plan to 1) investigate the profound effect mutations may bring to the structure and stability of chromones and phenotypes in ESCC cells and epithelia transformed cells; 2) screen the molecules interacted with the main function domains of AJUBA with antibody arrays; 3) screen lethal gene mutation with CRISPR technology. In this way, we may be able to elucidate the molecular mechanism of AJUBA in ESCC carcinogenesis and tumor progression, and evaluate its potential as a cancer biomarker and therapeutic target for ESCC.