WNT7B自分泌正反馈环路在胃癌转移中的作用

Gastric cancer is a highly aggressive cancer with high mortality, and is lacking for biomarkers and targeted therapies. Therefore, fully understanding the mechanisms of gastric cancer is critical for development of novel detection and treatment strategies. Although dysregulation of WNT signaling is implicated in the pathogenesis of gastric cancer, WNT7B, one of WNT ligands, has not been explored in gastric cancer. Recently we have found that WNT7B was up-regulated in gastric cancer and its expression levels are positively associated with gastric cancer metastasis; WNT7B could induce its own expression in gastric cancer cells, which was under the regulation of WNT/beta-catenin signal pathway. Therefore, we propose that the autocrine positive feedback loop of WNT7B promotes the progression of gastric cancer metastasis. Firstly, we will continue to analyze the specimens of gastric cancer to investigate the correlation between WNT7B expression and gastric cancer metastasis. Secondly, through exploring the autocrine positive feedback loop, we will illuminate the molecular mechanisms of WNT7B expression. Thirdly, with combined analysis of gastric cancer cells and mice models of gastric cancer, we will provide supporting evidence that the autocrine positive feedback loop of WNT7B plays an important role in gastric cancer metastasis. Thus, this project is expected to reveal unidentified novel functions and regulatory mechanisms of WNT7B, and to provide new therapeutic targets for the treatment against gastric cancer.

胃癌是一种侵袭性强且死亡率高的恶性肿瘤，却缺乏特异的诊断标志物和有效的靶向治疗药物。因此揭示胃癌侵袭转移的新机制必将给诊断与治疗带来新希望。目前已知WNT信号的过度活化能够推动胃癌的发生转移，然而配体WNT7B却尚未有在胃癌中的研究报道。申请者的前期研究发现：胃癌中WNT7B的表达量上调，且和转移正相关；WNT7B可以诱导胃癌细胞中自身的表达，而WNT/beta-catenin通路能够调控这种自分泌正反馈作用。由此，本项目提出假设：WNT7B通过自分泌正反馈环路促进胃癌转移。本项目拟通过分析临床胃癌标本，验证WNT7B表达与胃癌转移的相关性；通过阐明WNT7B的自分泌正反馈环路，揭示WNT7B上调表达的分子机制；通过细胞实验及动物实验，论证WNT7B自分泌正反馈环路在胃癌中的功能。项目的完成将首次揭示WNT7B在胃癌中的作用与机制，为胃癌提供新型诊断标志物与治疗靶标。

胃癌的转移性强且预后差，却缺乏特异的标志物用于早期的诊断和精准的靶向治疗。尽管过度活化的Wnt/beta-catenin信号和上调的RNA m6A修饰已被报道能够促进胃癌的发展，但是具体的分子机制尚不明确。本项目首次发现胃癌中存在WNT7B-m6A-TCF4正反馈环路，Wnt/beta-catenin信号和RNA m6A修饰通过此环路相互增强共同推动胃癌转移。我们的研究发现，WNT7B既可以作为配体激活Wnt/beta-catenin信号促进beta-catenin入核，又可以通过降低FTO介导的RNA m6A去甲基化修饰上调TCF4的表达。同时，TCF4能够通过结合beta-catenin直接促进WNT7B的转录。在细胞水平，WNT7B和TCF4都能够促进胃癌细胞的增殖和迁移。在临床样本中，WNT7B和TCF4在胃癌组织中上调表达，且和胃癌病人的不良预后相关；而血清中WNT7B的含量随胃癌转移程度上调，具有作为非侵入诊断和检测胃癌的标志物的潜能。在动物水平，TCF4促进胃癌细胞的体内生长及转移；WNT7B能够促进来自于胃癌病人的肿瘤移植块的体内生长；另一方面，利用抑制剂破坏WNT7B-m6A-TCF4正反馈环路可以在体内治疗胃癌。因此，本项目揭示了WNT7B-m6A-TCF4正反馈环路促进胃癌发展和转移的功能，为胃癌的诊断和治疗提供了潜在靶点。