SK4在肝癌细胞增殖、细胞周期和血管新生中的调控机制的研究

New directions are required for the treatment of hepatocelluar caricinoma. The abnormally over expression of intermediate-conductance calcium-activated potassium channel（SK4）has been observed in multiple malignant tumors, in which the cell proliferation and cell cycle are also impacted. Based on our previous results that over expression of SK4 was observed in HCC cells and thus affected the proliferation and apoptosis of HCC cells,these steps are planned in this project for futher investigation: To study the effect and the molecular regulation mechanism of SK4 in proliferation and cell cycle of in vitro- cultivated HCC cells through specific activation and blockage of SK4 and the supression of SK4 gene transcription via shRNA interference plamid transfection. To establish HCC mouse model by using SK4 gene knock-out mice,to compare the blockage of SK4 channel and the knock-out of SK4 gene in the context of their effects on cell proliferation, cell cycle and angiogenesis,as well as the impact of these effects on down-stream signaling pathway. This project is intended to clarify the effects and molecular regulation mechanism of SK4 channel in the cell proliferarion, cell cycle and angiogenesis in HCC cells and thus to provide noval targets and strategies for the treatment of hepatocellular carcinoma.

肝癌（HCC）的治疗需要新的研究方向。中电导的钙激动钾离子通道（SK4）最近被发现在多种恶性肿瘤异常高表达，并影响肿瘤细胞增殖和细胞周期。我们的前期研究显示SK4在人HCC细胞中高表达并影响其细胞增殖和凋亡，本项目拟进行下一步深入研究：于体外培养的人HCC细胞中特异性激活和阻断SK4以及利用shRNA干扰质粒转染抑制SK4基因转录，研究体外培养HCC细胞中SK4在细胞增殖和细胞周期的作用及其分子调控机制；利用SK4敲基因小鼠建立HCC模型，比较研究阻断SK4通道以及敲除SK4基因对小鼠HCC细胞增殖和细胞周期以及肿瘤血管新生的影响，同时深入研究其对下游信号通路的影响。以期阐明SK4通道在HCC细胞增殖、细胞周期以及血管新生中的作用和分子调控机制，为肝癌的治疗提供新的治疗靶点和治疗策略。

中电导钙激动钾离子通道（SK4）最近发现在多种恶性肿瘤异常表达，并影响肿瘤细胞增殖和细胞周期。我们的研究显示：1) 原发性肝细胞癌组织中存在SK4的表达，其表达可能与肝细胞癌生理功能相关；2) SK4参与调控肝癌细胞的增殖、凋亡、细胞周期及恶性特征，明确了其在肝癌细胞生理活动中发挥的作用，并成功在体外利用通道调节剂干预离子通道，调控肝肿瘤细胞的恶性进程；3)成功探索了SK4与增殖、凋亡、细胞周期及细胞因子分泌相关信号通路之间的关系，并为SK4调控肿瘤细胞生理活动的作用提供了理论基础和实践证据，为SK4在体内治疗中的研究提供了理论基础。