P53-PXR-PrPc通路调控胃癌转移的机制研究

Metastasis is one of the main causes of gastric cancer (GC). Pregnane X receptor (PXR) was found to play critical roles in regulating multidrug resistance of cancer. The latest studies showed that PXR and its downstream molecules might be the potential modulators of caner invasion and metastasis. According to our previous researches, PXR was up-regulated in GC tissues, and its intensity was correlated with metastatic status of GC. In addition, we also analyzed PXR expression between primary GC tissues and corresponding metastatic lymph nodes and found that expression of PXR was significantly increased in metastatic lymph nodes than that in primary GC tissues. By in vitro functional studies, we noticed that the stimulation of PXR was associated with cancer cell motility, but this effect depended on the status of TP53 mutation in different GC cell lines. Further studies indicated that PXR might transactivate PrPc, a protein that was already found to regulate GC metastasis. On the basis of the information above, we speculated that P53-PXR-PrPc axis might play crucial roles in regulating GC metastasis. In this project, we aimed to clarify the potential mechanisms underlying the regulation of GC metastasis by PXR, and we also planned to fully evaluate the clinical significance of P53, PXR and PrPc in GC tissues. The outcomes of this project could provide evidence for PXR as a potential therapeutic target for GC.

胃癌的转移是造成胃癌预后不佳的主要原因。既往研究表明孕烷受体（PXR）是肿瘤多药耐药的重要调控分子，且最新的研究提示PXR是肿瘤侵袭和转移的潜在调控因素。我们通过免疫组化研究发现PXR在胃癌组织中表达升高，且其表达强度与胃癌的转移情况相关。与原发灶相比，PXR在胃癌转移淋巴结中的表达水平亦显著升高。体外功能学实验证实， PXR的激活可增强携带突变型P53的胃癌细胞的转移能力，而携带野生型P53 的胃癌细胞的转移能力在PXR激活前后并未发生显著变化。以上提示PXR可能参与了胃癌的转移，且这种现象可能与P53密切相关。进一步研究表明PXR可能转录激活胃癌转移的调节分子朊蛋白（PrPc），这提示PrPc可能是PXR的下游通路节点分子。因此，本项目拟进一步明确PXR调节胃癌转移的机制，同时还将阐明P53是否可作为PXR的上游调控分子。本项目有助于为胃癌的治疗提供新的潜在靶点。

胃癌的转移是造成胃癌预后不佳的主要原因。既往研究表明孕烷受体（PXR）作为核受体的一种，是调控肿瘤多药耐药的重要分子。同时，也有研究表明PXR也是肿瘤侵袭和转移的潜在调控因素。然而，PXR在胃癌中的作用尚不清楚。本课题以PXR和胃癌转移的关系为主要研究方向，以阐明PXR的功能和分子作用机制。本课题的主要研究内容包括：验证PXR对胃癌转移的直接调控作用；探索PXR通过其转录活性靶向作用于PrPc的分子机制；验证P53对PXR转录活性的调控作用；明确以PXR为核心的胃癌转移调控通路在胃癌中的表达和临床意义。通过上述研究，获得了以下重要研究结果：1. 上调PXR可显著促进胃癌的运动能力，下调PXR可显著胃癌细胞的运动能力；2. PXR可结合于PrPc的启动子区，通过转录激活作用调节PrPc的表达；3. 野生型的P53抑制PXR的转录激活能力，突变型的P53促进PXR的转录活性；4. PXR在胃癌组织中的表达升高，其表达在淋巴结转移灶中的表达强度均高于相应原发灶组织，PXR的升高提示胃癌患者总生存期缩短。以上结果对阐明PXR的作用及调控机制具有重要意义，有助于深化对P53-PXR-PrPc在肿瘤发生发展过程中所发挥作用的理解，对寻找胃癌转移的潜在治疗靶标奠定了基础。