膀胱癌的高异质性、多中心生长及易复发等特性导致其治疗棘手。预实验发现CDC7在膀胱癌中高表达，干扰CDC7后膀胱癌细胞核形态改变，出现细胞衰老表型及细胞增殖和运动迁移能力下降。过表达CDC7突变体（K90A）后，发现CDC7的功能依赖其激酶活性。IP-MS和磷酸化蛋白质组学检测发现CDC7磷酸化LMNA-S22位点。文献显示LMNA磷酸化缺陷介导细胞核形态改变诱导细胞衰老，而细胞衰老抑制肿瘤。据此提出假设：膀胱癌中高表达的CDC7通过磷酸化LMNA使细胞核形态稳定，抑制细胞衰老，促膀胱癌发生发展。为此拟进行：CDC7临床回顾性研究；体内外实验探究CDC7促膀胱癌发生发展的功能；利用抑制剂、挽救实验等技术探究膀胱癌中CDC7通过磷酸化LMNA维持细胞核形态，抑制细胞衰老，促膀胱癌发生发展的机制，有望为细胞衰老抗肿瘤，尤其是为P53和RB突变导致传统细胞衰老通路关闭的肿瘤的药物开发提供新方向。

The high heterogeneity, multicentric growth and recurrence characteristics of bladder cancer make the treatment difficult. In preliminary experiments, we found that CDC7 was over expressed in bladder cancer, and the nuclear morphology of bladder cancer cells was changed, cell senescence phenotype was induced and the cell proliferation and motility were inhibited after the interference of CDC7 in bladder cancer cells. Notably, we found the function of CDC7 in bladder cancer cells was dependent on its kinase activity after the up regulation of CDC7 mutant (K90A). Furthermore, the phosphorylation of LMNA-S22 site could be regulated by CDC7 in IP-MS assay and quantitative iTRAQ-based phosphoproteomic analysis. It was reported that the defects of phosphorylation of LMNA mediated the changes of cell nuclear morphology resulting in cell senescence, and cell senescence could suppresses tumor occurrence and progression. Based on our preliminary experiments results and literature evidence, we propose that the overexpression of CDC7 in bladder cancer inhibits cell senescence through stabilizing cell nuclear morphology mediated by LMNA phosphorylation, which can promote the occurrence and progression of bladder cancer.Thus, we plan to: (1) conduct the clinical retrospective analysis of CDC7; (2) verify the function of CDC7 in promoting the proliferation and migration of bladder cancer cells in vitro and in vivo; (3) investigate the mechanism of CDC7 inhibiting cell senescence through maintaining cell nuclear morphology mediated by LMNA phosphorylation in promoting the occurrence and progression of bladder cancer using inhibitors and rescue experiment, etc. Clarifying the mechanism of CDC7 in promoting the occurrence and progression of bladder cancer may provide a new strategy for the development of anti-tumor drugs by inducing cell senescence, especially for tumor with P53 mutation or RB mutation which leads to the closure of traditional cell senescence pathway.