候选抑癌基因RCBTB2通过调控初级纤毛形成抑制肝癌细胞生长的分子机制

RCBTB2 is a member of the RCC1 (Regulator of Chromosome Condensation 1) protein superfamily. It was reported that the chromosome region 13q14.2, within which RCBTB2 is located, is deleted in both B-cell chronic lymphocytic leukemia and prostate cancer, suggesting RCBTB2 as a tumor suppressor gene, with the molecular mechanism largely unknown. In our previous study, 49 percent of the examined liver cancer tissues present either homozygous or heterozygous loss of RCBTB2 gene, accompanied with reduction in the levels of both mRNA and protein. Furthermore, reduced RCBTB2 expression is correlated with poor differentiation of liver cancer, and suppression of the gene’s function results in defected primary cilium and promotes growth of tumor cell. Therefore we hypothesized that RCBTB2 can regulate tumorigenesis in liver, probably through its roles in primary cilium formation. In this study, focusing on RCBTB2 and its related proteins, we will utilize yeast two-hybrid and proteomics technology to identify novel proteins interacting with RCBTB2, and reveal the roles of RCBTB2 and its interacting proteins in signaling pathways regulating cell proliferation. Then through molecular biology methods and model mice , we will clarify the functions of RCBTB2 in tumorigenesis of liver cancer and the associated mechanisms, and finally discover a novel molecular target for both diagnosis and targeted therapy for liver cancer.

RCBTB2是RCC1蛋白超家族的一个成员。文献报道淋巴细胞性白血病和前列腺癌中13q14.2区域缺失，而该区域包含RCBTB2基因，推测RCBTB2可能是肿瘤抑制因子，但分子机制很不明确。我们前期研究发现在49%的肝癌中RCBTB2存在纯合/杂合型缺失，并伴随其mRNA及蛋白表达量下调；临床病理相关性分析发现RCBTB2低表达与肝癌不良分化相关；抑制RCBTB2影响初级纤毛形成并促进肝癌细胞生长。据此我们推测RCBTB2可能通过调控初级纤毛形成抑制肝癌细胞生长。本研究将以RCBTB2为中心，以RCBTB2与相关蛋白的相互作用和调节为主轴，利用酵母双杂交和蛋白组学技术发现新的RCBTB2相互作用因子；明确RCBTB2与互作因子参与调控细胞增殖的信号转导过程；采用分子、细胞、模式动物等方法阐明RCBTB2在肝癌发生中的作用及分子机制，发现新的分子靶点，为肝癌的分子诊断及靶向治疗提供理论依据。

RCBTB2是RCC1蛋白超家族的一个成员。文献报道淋巴细胞性白血病和前列腺癌中13q14.2区域缺失，而该区域包含RCBTB2基因，推测RCBTB2可能是肿瘤抑制因子，但分子机制很不明确。.我们的研究发现在肝癌组织中RCBTB2蛋白表达量下调；临床病理相关性分析发现RCBTB2低表达与肝癌不良分化相关，RCBTB2低表达与肝癌患者较差的生存预后相关。细胞功能实验、小鼠原发性肝癌模型均证实，RCBTB2抑制肝癌细胞增殖生长，而RCBTB2的缺失可以显著促进肝癌的发生发展。我们筛选了RCBTB2的相互作用蛋白，并发现RCBTB2可以通过其BTB结构与结合BEX3，并促进BEX3的蛋白降解从而调控其蛋白质稳定性。.我们的研究说明，RCBTB2是一个肿瘤抑制基因，其可以通过结合并介导BEX3的降解抑制肝癌细胞的增殖生长，抑制肝癌的发生发展，从而为肝癌的分子诊断提供了新的生物标志物，并为肝癌的治疗提供了一个潜在的治疗靶点。