细胞周期调节因子KCTD12的发现及其调控机制

Dysregulation in cell cycle leads to uncontrolled proliferation and tumorigenesis, but the underlying mechanisms remain to be elucidated. Understanding of the molecular mechanisms in cell cycle progression can provide clues for identification of the key proteins involved in cancer development. In this study, cell synchronization along with quantitative proteomics were performed to identify novel regulators of cell cycle. Potassium channel tetramerization domain containing 12 (KCTD12) was found to be significantly upregulated in M phase compared with S phase. We have found that KCTD12 overexpression not only facilitated G2/M transition and induced cancer cell proliferation, but also promoted growth of subcutaneous tumors. Next we will conduct further research on the founction of KCTD12 and the mechanism how KCTD12 exerts its effect, especially the cellular localization and interactive proteins. Furthermore, gene expressions and correlation with survival will be analyzed in tumor tissue microarray, and small molecular inhibitor of KCTD12 will be screened to provide more clues on anti-tumor drug development.

细胞周期调节失控是导致细胞恶性增殖和肿瘤发生的重要原因，深入研究细胞周期调控的分子机制，有助于充分认识肿瘤的本质，了解癌症的发生机制，为癌症的早期诊疗提供分子靶标。本研究拟根据前期建立的细胞周期同步化模型，结合定量蛋白质组学技术系统地分析比较S期和M期的细胞周期蛋白，着重探讨新发现的潜在细胞周期调控因子KCTD12的功能和分子机制。前期实验中，我们发现并验证了KCTD12表达量在M期显著增加，细胞实验证实KCTD12能够促进细胞分裂和肿瘤细胞增殖，动物实验也证实KCTD12对肿瘤的发生发展有重要的促进作用；下一步将深入探讨KCTD12调控细胞周期的机理及其与肿瘤的相关性。通过分析其相互作用蛋白，绘制KCTD12发挥功能的信号通路，并在临床组织水平验证KCTD12的含量与肿瘤恶性程度的关系；最后针对KCTD12的功能机制进行小分子抑制剂的筛选，为日后开发细胞周期相关抗肿瘤药物提供基础。

细胞周期调节失控是导致细胞恶性增殖和肿瘤发生的重要原因，深入研究细胞周期调控的分子机制，有助于充分认识肿瘤的本质，了解癌症的发生机制，为癌症的早期诊疗提供分子靶标，为抗癌药物的开发提供重要线索。本项目基于细胞周期同步化模型，结合定量蛋白质组学技术系统地分析比较了S期和M期的细胞周期蛋白，着重探讨新发现的细胞周期调控因子KCTD12的功能和分子机制。我们发现并验证了KCTD12表达量在M期显著增加，细胞实验证实KCTD12能够促进细胞分裂和肿瘤细胞增殖，动物实验也证实KCTD12对肿瘤的发生发展有重要的促进作用，深入的分子机制研究表明KCTD12通过激活Aurora-A/CDK1信号通路而促进细胞周期的进行。临床组织病理学分析表明KCTD12与肿瘤恶性程度显著相关，随后根据CDK1-KCTD12的相互作用关系筛选出了小分子抑制剂adefovir dipivoxil，深入的研究表明该抑制剂能够显著抑制肿瘤细胞增殖并逆转肠癌细胞的vemurafenib耐药。本项目不仅为肿瘤的诊断提供了新颖的标志物KCTD12，也为癌症治疗提供了潜在的靶向药物Adefovir dipivoxil，具有重要的临床应用价值。