金黄色葡萄球菌PV杀白细胞素S组分靶向C5aR下调HDAC6在抑制肝癌细胞上皮间质转化中的作用和机制研究

上皮间质转化（EMT）是肝癌侵袭转移的重要分子事件。文献报道，补体C5a受体（C5aR）在肝癌细胞中呈高表达，并与EMT进程相关。我们前期研究发现金黄色葡萄球菌PV杀白细胞素S组分（LukS-PV）能靶向结合C5aR，抑制肝癌细胞EMT，并可下调组蛋白去乙酰化酶6（HDAC6）表达；同时发现在肝癌细胞中敲低HDAC6能逆转EMT。推测LukS-PV可能通过C5aR下调HDAC6发挥逆转肝癌细胞EMT生物学效应。本课题拟：1、使用体内、外实验研究C5aR和HDAC6在LukS-PV逆转肝癌EMT中的作用。2、揭示LukS-PV通过C5aR下调HDAC6的分子机制。3、研究LukS-PV下调HDAC6在抑制肝癌EMT中的作用机制。以上研究有望阐明C5aR、HDAC6是LukS-PV逆转肝癌EMT的关键分子，可作为LukS-PV靶向治疗和疗效评价的分子标志物，为LukS-PV临床应用奠定基础。

Epithelial-mesenchymal transition (EMT) plays a critical role in invasion and metastasis in hepatocellular carcinoma (HCC). Recent studies indicate that complement C5a receptor (C5aR) is significantly upregulated in HCC and the high expression of C5aR was closely correlated with EMT. Our previous studies found that a component of Panton-Valentine leukocidin secreted by Staphylococcus aureus (LukS-PV) could bind C5aR, inhibit EMT progress and down-regulate the expression of histone deacetylase 6 (HDAC6) in HCC cells. Furthermore, knocking down HDAC6 could reverse EMT. Therefore, we hypothesiz that LukS-PV may reverse EMT through targeting C5aR to decrease HDAC6. This project aims to: 1. further verify the role of C5aR and HDAC6 in reversing EMT by LukS-PV in vivo and in vitro; 2. reveal the molecular mechanism how LukS-PV down-regulates the expression of HDAC6 through C5aR; and 3. uncover the mechanisms how downregulation of HDAC6 regulated by LukS-PV can reverse the EMT in HCC. Our studies are expected to elucidate whether C5aR and HDAC6 are key targets during the process of LukS-PV reversing EMT in HCC and whether they can serve as the molecular markers for targeted therapy of LukS-PV and the resultant efficacy evaluation. Our studies will lay a foundation for future clinical application of LukS-PV.