长链非编码RNA-H19诱导胃癌相关成纤维细胞活化的机制研究

Gastric cancer associated fibroblasts (GCAF) are important regulators of gastric cancer, and is expected to become the new target for tumor interstitial therapy. The mechanism of GCAF activation play an important role in improving the prognosis of gastric cancer. Our former researches and literature review suggested lncRNA-H19 involved GCAF activation process. But the e mechanism of GCAF activation is not clear until now. Therefore our study would further discuss the mechanism of GCAF activation and explore the inductive effects of lncRNA-H19 in the progression of GCAF activation on the basis of constructing multiple factors induced gastric cancer mice model. And we also want to verify the lncRNA-H19 would enhance the proliferation and invasion of tumor cells by induction of GCAF activation. Use the goal lncRNA/target mRNA interaction model between the structure and function to confirm the exact target of lncRNA - H19 in GCAF activation. We aimed to clarify the mechanism of the inductive effects of lncRNA - H19 in GCAF activation which would provide theoretical and experimental basis for new therapeutic targets in the clinical treatment in gastric cancer.

胃癌相关成纤维细胞（GCAF）是肿瘤发生发展的重要调控者，并有望成为肿瘤间质治疗的新靶点，研究GCAF活化的具体机制对于改善胃癌预后具有很重要的理论和临床意义。本课题组的前期研究及文献调研均提示lncRNA-H19参与了GCAF的活化过程，但其对于GCAF活化的调控机制目前尚不清楚。因此本研究拟通过构建小鼠多因素诱导胃癌模型，进一步探讨GCAF在胃癌发生和发展过程中发生活化的具体机制，并观察lhnRNA-H19在GCAF活化过程中的作用，证实lhnRNA-H19可诱导的GCA活化，从而提高肿瘤细胞增殖和侵袭性。并经目标lncRNA/靶mRNA间相互作用的结构和功能学验证，确认参与GCAF活化的lncRNA-H19的直接调控靶点。通过研究lncRNA-H19表达对GCAF活化状态的影响，证实lncRNA可以成为逆转GCAF活化状态的治疗靶点，为临床探索胃癌新的治疗靶点提供理论依据和实验基础。

胃癌相关成纤维细胞（GCAF）是肿瘤发生发展的重要调控者，目前已成为肿瘤间质治疗的新靶点，研究GCAF活化的具体机制对于改善胃癌预后具有很重要的理论和临床意义。本课题组的前期研究及文献调研均提示lncRNA-H19参与了GCAF的活化过程，因此，本研究在构建多因素诱导小鼠胃癌的基础上研究lncRNA-H19和GCAF活化的关系及其相关机制。研究发现，在GCAF的活化过程中，lhnRNA-H19会呈现明显的上调；而在lhnRNA-H19条件性敲除的小鼠诱导的胃癌模型中，GCAF活化明显受到抑制。同时对条件性敲除小鼠的胃癌组织进行lncRNA的筛查发现，lncRNA-MEF2C和FENDDER的表达均明显下降，提示lhnRNA-H19可能通过上调lncRNA-MEF2C和FENDDER的表达上调进而参与GCAF的活化。本研究的结果提示lncRNA-H19可以成为逆转GCAF活化状态的治疗靶点，为临床探索胃癌新的治疗靶点提供理论依据和实验基础。