FAT4在胃黏膜细胞恶性转化中的功能及机制研究

Understanding the mechanism of gastric mucosa malignant transformation is important,which is conducive to early detection and the improvement of prognosis.In our previous study,it was found that FAT4 was a tumor suppressor gene in gastric cancer,and down-regulating FAT4 could activate the β- catenin/TCF signaling pathway and promote gastric cancer cell tumor formation and metastasis, but the specific regulatory mechanism was unknown.It is known that Wnt/β-catenin signal is an important factor in gastric mucosa malignant transformation. And some reports showed that FAT4 methylation was detected in the normal gastric mucosa adjacent to gastric cancer, and inhibiting FAT4 expression could drive normal breast epithelium cells malignant transformation.Therefore, we hypothesized that: FAT4 may participate in the gastric mucosa malignant transformation, down-regulating FAT4 can activate the β-catenin/TCF signal. We will use the clinical specimens to identify FAT4 expression in different stages of gastric cancer occurrence. By using cell model, animal models, molecular biology technology to clarify FAT4 effects on gastric mucosa malignant transformation and the specific regulatory mechanism of β- catenin/TCF signal pathway. Our study will deepen the understanding of the mechanism of cancerization in stomach,and provide new targets for prevention and treatment of gastric cancer.

研究胃黏膜恶性转化的分子机制，利于筛选胃癌早期预警及防治关键节点、改善预后。我们前期已鉴定FAT4在胃癌中起抑癌基因作用，下调FAT4可激活β-catenin/TCF信号通路促进胃癌细胞的成瘤和转移能力，但具体调控机制不明。由于Wnt/β-catenin信号激活是胃黏膜恶性转化的重要因素，已知抑制FAT4表达可导致小鼠乳腺正常上皮细胞恶性转化，正常胃黏膜及癌旁胃黏膜中FAT4甲基化水平与幽门螺杆菌感染和胃癌发病风险密切相关。我们推测：FAT4很可能参与了胃黏膜细胞恶性转化，下调FAT4表达通过激活β-catenin/TCF信号促进胃癌发生。我们将利用临床标本进一步明确FAT4在胃癌发生不同阶段的表达情况；利用细胞模型、动物模型、分子生物学技术阐明FAT4对胃黏膜恶性转化作用和对β-catenin/TCF信号通路具体调控机制。该研究将加深对胃癌发生机制的认识，为胃癌防治提供新靶点。

胃癌发生率在最常见的恶性肿瘤中排名第五位，死亡率处于第三位。衰老相关干性是一种细胞自主特征，在从细胞静息中逃脱时发挥其高侵略性的生长潜力，并且在复发性肿瘤中富集，可能是肿瘤细胞化疗后耐药复发的机制之一。化疗可引起肿瘤细胞衰老，从衰老释放的细胞能够重新进入细胞周期，与同样暴露于化疗，但从来没有衰老过的群体相比，具有强烈增强的和Wnt依赖的克隆生长潜力。Wnt信号通路包括经典和非经典信号通路，经典的Wnt/β-catenin信号通路在胃癌的发生和转移发生中起着重要作用。FAT4属于FAT家族，编码产物属于钙离子依赖的粘附分子，在胃癌的发生过程中常发生表达下调。我们初步的实验结果表明，FAT4在配对的胃癌组织样本中表达下调，并且FAT4的表达水平与肿瘤病人的生存时间显著相关。在胃癌细胞中下调FAT4的表达促进胃癌细胞的迁移、浸润及其在裸鼠体内的转移能力。进一步研究发现，下调FAT4的表达激活beta-catenin/TCF信号通路，调控一系列EMT标记分子的表达。本项目中，我们进一步研究了FAT4对beta-catenin/TCF信号通路具体调控机制，及其在诱导胃癌细胞衰老过程的作用机制。为加深对胃癌发生发展机制的认识，阐明FAT4蛋白功能异常在胃癌细胞中的作用，为胃癌的治疗提供新的靶点。