ATOH8介导层流切应力调控胃癌血行转移的机制研究

肿瘤微环境是影响胃癌转移的重要因素，而力学因素作为微环境的重要组成部分，在肿瘤转移中的作用渐受重视。层流切应力（LSS）是影响循环肿瘤细胞（CTCs）的主要力学形式，与CTCs形成转移灶的关系有待阐明。ATOH8的表达在正常细胞中受LSS调控，但是尚未见在肿瘤细胞中的报道。我们的前期研究发现：LSS刺激或过表达ATOH8抑制胃癌细胞的增殖和干性，促进胃癌细胞凋亡，介导周期停滞；LSS也可上调胃癌细胞ATOH8表达。生物信息学分析表明FOXO3（和/或NF-kB）可能是LSS上调ATOH8的信号通路。因此，本项目旨在探讨力学因素抑制胃癌血行转移的机制，通过体外模拟LSS环境，观察不同梯度LSS对胃癌细胞增殖、凋亡、周期和干性的影响，阐明LSS通过上调ATOH8抑制胃癌血行转移的信号通路，并在动物模型上予以验证，以期从力学微环境角度为胃癌血行转移提供新的分子生物学依据和潜在的治疗靶点。

Tumor microenvironment plays an important role in the tumor metastasis. Mechanical properties which serve as an important part of tumor microenvironment has been attracting attention for its role in tumor metastasis. Laminar shear stress （LSS）was the main mechanical form affecting circulating tumor cells（CTCs), but its effect on CTCs forming metastasis has been unclear. ATOH8 was a newly identified laminar-shear-stress-responsive transcription factor. Researches on the role of ATOH8 in tumor have just started. Our preliminary experiment showed that both LSS stimulation or ATOH8 overexpression could inhibit proliferation and stemness, promote apoptosis and induce cycle arrest of gastric cancer (GC) cell; LSS could upregulate ATOH8. Bioinformatic analysis suggested that FOXO3(and /or NF-kB) might participate in the process of LSS inducing ATOH8 upregulation; ATOH8 might also serve as a direct transcriptional factor of BMP family. Thus we proposed that LSS could inhibit metastasis of GC; ATOH8 was the bridge molecular linking LSS to GC metastasis. This project aims to clarify the molecular mechanism under LSS inhibiting gastric cancer metastasis via upregulating ATOH8, by simulating the mechanical properties of tumor microenvironment in vivo, as well as by using cell function experiments, molecular biological experiments and animal models. Finally, this project would provide a brand new molecular basis for the signal regulation of GC metastasis in terms of mechanal microenvironment.