转录因子TCF21靶向E-Cadherin调控胃癌侵袭转移的研究

Gastric cancer remains a major public health issue as one of the most common digestive malignancies. The poor prognosis is mainly due to its strong local invasion and distant metastasis in early stage. Epithelial-to-mesenchymal transition (EMT) has been proven essential for the dissemination and metastasis of malignant tumors. Therefore, explore the key molecules associated with EMT play an important role in clarifying the mechanism of tumor invasion and metastasis in gastric cancer.Candidate tumor suppressor gene TCF21 encodes a basic helix-loop-helix transcription factor. It mandates cell fate differentiation through mesenchymal–epithelial transition (MET). Our previous study showed that the expression of TCF21 in gastric carcinoma tissues was significantly lower than the adjacent normal gastric mucosal tissues. The Kaplan–Meier survival analysis showed that TCF21 expression was an independent prognostic factor of cancer-specific survival. We also found the expression of TCF21 was positively correlated with E-cadherin. There is a potential connection between TCF21 and EMT，but the mechanism was poorly understood. On the basis of our earlier work, we propose to assess the biological function and detailed molecular mechanism underlying TCF21 in gastric cancer by molecular, cellular, and animal model studies. We believe such an investigation will reveal the molecular mechanisms of gastric cancer progression and provide newly targeted therapeutic strategies to prevent gastric cancer.

胃癌作为常见的消化道恶性肿瘤严重危害公众健康。早期即可发生转移，是其死亡率高、预后差的主要原因。上皮细胞-间充质转化(EMT)是恶性肿瘤发生侵袭和转移的早期必要条件。故探索胃癌中基于EMT的关键分子，对阐明胃癌侵袭和转移的具体机制至关重要。候选抑癌基因TCF21编码碱性螺旋-环-螺旋转录因子，通过调控间充质细胞-上皮转化（MET）调控细胞分化。我们前期研究发现TCF21在胃癌组织中的表达显著低于癌旁正常胃粘膜组织，生存分析发现TCF21表达是胃癌患者的独立预后因素。同时发现其表达与E-钙粘蛋白呈正相关，与EMT存在潜在联系，但具体调控机制尚不清楚。本项目在前期工作基础上，拟在分子、细胞、组织、动物整体水平对TCF21在胃癌中的生物学作用及其在胃癌EMT中的调控机制进行探索性研究，丰富EMT调控网络，以期为胃癌的发生及转移的防治提供新的策略。

转录因子21（TCF21）是一种碱性螺旋-环-螺旋转录因子，其与DNA结合并在发育过程中通过间充质-上皮转化调节细胞生长和分化。TCF21基因在多种人类癌症中表观遗传学失活，并发挥广泛作用，包括调节上皮-间质转化，侵袭，转移，细胞周期和自噬等。我们前期研究发现TCF21在胃癌组织中的表达显著低于癌正常胃粘膜组织，生存分析发现TCF21表达是胃癌患者的独立预后因素。本课题通过体内体外研究进一步探索了其在胃癌中的作用及其可能的调控机制。研究发现，TCF21在胃癌中作为一种肿瘤抑制基因，DNA甲基化是其在胃癌中失活的主要机制。TCF21在体外和体内抑制胃癌的增殖，侵袭和迁移。TCF21还通过AKT / Bcl-xL信号通路调节线粒体膜电位促进CDDP诱导的细胞凋亡，进而增加化疗敏感性。本课题的研究成果丰富了TCF21在肿瘤进展中的生物学作用及其可能的调控机制，为胃癌的分子靶向治疗提供了潜在的靶点。