KLF4在调节LXR信号通路抑制皮肤鳞癌增殖中的作用研究

Liver X receptors is one of important trasncription factors, invovled in various biological process, including lipid metabolism and barrier formation. The dysfunction of LXR signal may contribute to several hyperplasia cutaneous diseases.however, the exact role and corresponding mechanism of the dysfunction and skin carcinogenesis remains unclear.Recent researches have demonstrated that activation of LXR signal inhibited cell growth in several carcinoma cell lines.Consistent with those researches, we found evidence for Liver X Receptor β involvement in the pathogenesis of SCC. Additionally, our preliminary data strongly indicates that Kruppel-like factor 4 (KLF4) is highly upregulated in response to LXR agonist treatment, as well as its target gene-p21. Therefore, we can highly postulate that KLF4 might play an important role in regulating the growth inhibition induced by LXR signal activation.In this project we intend to study the role and the mechanisms of KLF4 in regulating the LXR signal by using RNAi,EMSA and other methods in A431 cells. Through our study, we expect to provide theoretical support and guidance for the prevention and theraputical applications for cutaneous cancers.

体内胆固醇感受器LXRs，在调节皮肤脂质代谢及屏障功能形成方面发挥重要作用。该受体信号功能失调可能参与多种增殖性疾病的发生发展过程。目前众多研究发现激活LXR信号通路，可抑制多种肿瘤细胞株的增殖，可能成为肿瘤预防和治疗的关键靶点，本项目的前期研究发现LXR激动剂可通过受体依赖方式，诱导体外培养A431细胞出现细胞周期停滞，抑制体外培养皮肤肿瘤细胞增殖。此外，基因芯片结果提示KLF4在LXR激动剂处理后细胞中表达明显升高，且其升高趋势与细胞周期抑制因子p21趋势一致，因此有理由推测KLF4在调节LXR信号途径抑制皮肤鳞状细胞癌的增殖过程中发挥重要作用。本项目拟采用RNAi、EMSA等方法，观察KLF4在调节LXR信号途径中的关键作用，明确LXR在皮肤肿瘤中的作用以及可能的分子机制，可为皮肤肿瘤的预防和治疗提供更多选择。

体内胆固醇感受器LXRs，在调节皮肤脂质代谢及屏障功能形成方面发挥重要作用。该受体 信号功能失调可能参与多种增殖性疾病的发生发展过程。目前众多研究发现激活LXR信号通路 ，可抑制多种肿瘤细胞株的增殖，可能成为肿瘤预防和治疗的关键靶点，本项目研究发现LXR在皮肤鳞癌组织中的表达明显高于正常组织，体外实验中LXR激动剂可通过受体依赖方式，诱导体外培养皮肤鳞状细胞癌细胞系(A431细胞和SCL-1细胞)出现细胞周期停滞，从而抑制体外培养皮肤肿瘤细胞增殖。此外，基因芯片结果提示KLF4在LXR激动剂处理后细胞中表达明显升高， 且其升高趋势与细胞周期抑制因子p21趋势一致，双荧光素酶报告基因系统检测结果发现，LXR激动剂可使转染有KLF4启动子质粒的细胞荧光值明显升高，提示LXR激动剂可直接激活KLF4转录，因此KLF4在调节LXR信号途径抑制皮肤鳞状细胞癌的增殖过程中发挥重要作用。LXR激动剂可明显导致细胞周期停滞，抑制体外培养皮肤鳞状细胞癌细胞系(A431细胞和SCL-1细胞)细胞增殖，未来可能成为治疗皮肤肿瘤的又一特异性选择。