HoxB9诱导间皮细胞上皮化（MET）抑制胃癌侵袭转移机制的研究

Our previous studies found the expression of homeobox gene HoxB9 was suppressed in gastric cancer. Overexpression of HoxB9 suppressed proliferation, migration and invasion of GC though inducing MET. HoxB9 regulated MET of GC through its hexapeptide motif. This study is expected to elucidate the correlations between the expression of HoxB9 and MET markers in clinical pathology of GC, exploring the relationship between HoxB9 and GC’s metastasis, whether HoxB9 can predict GC’s prognosis. HoxB9 can be regulated by Pbx1, whether hexapeptide motif is a key site in which pbx1 interacts with HoxB9 needs to be demonstrated. Otherwise, the mechanisms through which the interaction of Pbx1-HoxB9 regulates MET and its downstream signaling pathways remain unclear. Further studies are expected to reveal the mechanisms by which Pbx1 interacts with HoxB9 to deliver upstream signals, find the most important signaling pathway and key genes regulated by HoxB9, and demonstrate how HoxB9 regulate key genes. Based on the analysis of hexapeptide motif sequence, we can develop small molecule compound to suppress proliferation, migration and invasion in GC. Animal experiments will be used to confirm how HoxB9 impacts GC’s subcutaneous implanted tumor growth and peritoneal metastasis ability. This study is supposed to provide evidences for developing new strategies of clinical diagnosis and therapy.

本课题组前期发现HoxB9在胃癌组织中表达缺失，过表达HoxB9通过诱导间皮细胞上皮化（MET）抑制胃癌细胞增殖、迁移与侵袭。HoxB9通过其六肽结构域调控胃癌MET。后续拟进一步研究胃癌临床病理中HoxB9与MET分子标志物的相关性，探讨HoxB9与胃癌转移的相关性，与胃癌患者的预后是否相关；揭示上游信号通过Pbx1与HoxB9之间的相互作用调控胃癌发生发展的分子机制，探讨六肽结构域是否Pbx1调控HoxB9的关键位点；寻找HoxB9下游直接受其调控的MET相关信号通路及关键基因，并分析HoxB9如何调控关键基因；分析六肽结构域的序列信息，并设计相应的小分子化合物，以抑制胃癌的增殖，迁移及侵袭；通过动物实验，探讨HoxB9对胃癌细胞皮下成瘤及腹腔转移能力的影响。本研究不仅有助于揭示HoxB9抑制胃癌作用的机制，还可以为胃癌相关的临床诊疗策略提供新思路。

胃癌是消化道常见的恶性肿瘤，在中国其发病率及死亡率一直居高不下，影响胃癌预后的主要原因是复发和转移，而胃癌转移的分子调控网络尚未阐明。本项目前期围绕同源盒基因PBX1/HoxB9结构特点及在胃癌中的作用展开研究，阐明了PBX1与HoxB9之间的相互作用调控胃癌发生发展的分子机制。证实了PBX1 在胃癌组织中高表达，其表达差异与组织分化，有无淋巴结转移相关。PBX1通过诱导上皮细胞间质转化促进胃癌细胞的转移，PBX1的Phe252片段在胃癌转移中起重要角色。HoxB9通过抑制Akt的磷酸化水平和NF-kB的活性以抑制胃癌细胞的增殖，HoxB9可抑制NF-kB依赖的Snail的表达，为胃癌转移的提供新的调控机制。同时，本课题证实OSMR在胃癌组织中高表达，其表达量与临床预后密切相关。。OSM-OSMR可以促进胃癌细胞侵袭，迁移以及上皮间充质转化。胃癌中OSM-OSMR可以促进STAT3、FAK以及SRC等通路的激活。分别靶向STAT3、FAK以及SRC可以发现OSM-OSMR可以激活STAT3/FAK/SRC 轴，OSMR可以被开发成为新的治疗靶点。lncRNA-UCA1可通过诱导GRK2蛋白的降解以促进胃癌细胞的转移。lncRNA-UCA1通过促进GRK2泛素化和降解来调节GRK2蛋白的稳定性。这一过程激活了ERK-MMP9信号通路。本项目为胃癌转移提供了多个调控机制及治疗靶点，具有重要的科学意义和良好的应用前景。