TOPK调控YB1促进食管鳞癌增殖的分子机制研究

Esophageal squamous cell carcinoma (ESCC) is the major type of esophageal cancer. Abnormal activation of several signal pathways is closely associated with the development of ESCC. Therefore, identification of new therapeutic targets by screening these important signaling proteins is a privtal way for ESCC treatment. T-LAK cell-originated protein kinase (TOPK) is a newly discovered serine-threonine kinase and participates in the processes of tumor initiation, progression and metastasis by activating different signaling pathways in a variety of tumors, such as breast cancer, lung cancer and colon cancer. However, the role and mechanism of TOPK in esophageal cancer is still unclear. Our previous results have indicated that TOPK was highly expressed in human ESCC tissues compared with normal esophageal tissues adjacent to carcinoma and overexpression of TOPK was sincerely related with poor prognosis in ESCC patients. Meanwhile, knocking down TOPK inhibited the proliferation and colony formation of esophageal cancer cell lines. We also found that dysregulated TOPK could modify many signaling pathways. Y box protein (YB1) may be demonstrated as TOPK substrate. Using multiple techniques such as computer modeling, protein kinase assay, mass spectrometry and animal models, this study will explore the molecular mechanism that TOPK promotes the proliferation of ESCC cells through regulating YB1. It will be very important for understanding the molecular mechanism of ESCC and also for the evaluation of TOPK as a therapeutic target for ESCC treatment.

食管鳞状细胞癌是我国食管癌的主要类型，其发生发展过程与多个信号通路的异常激活有关，筛选信号通路中的关键分子作为治疗靶点是食管鳞癌临床治疗的新策略。T-LAK细胞来源的蛋白激酶（TOPK）是一种丝氨酸-苏氨酸蛋白激酶，在乳腺癌、肺癌和结肠癌等不同的肿瘤中通过激活不同的信号通路参与肿瘤的发生发展和转移，而TOPK在食管鳞癌中的作用及其机制并不清楚。课题组前期研究发现TOPK在食管鳞癌组织中高表达，和患者的预后呈负相关。下调TOPK可以抑制食管鳞癌细胞的增殖和克隆形成并调控多个信号转导通路，且初步证实Y盒子结合蛋白1（YB1）是TOPK激酶的作用靶点。因此，本研究拟通过计算机模拟技术、蛋白激酶芯片、质谱技术、动物模型进一步探讨TOPK调控YB1促进食管鳞癌细胞增殖的分子机制。该研究有助于深入了解食管鳞癌的发生机制，为TOPK成为食管鳞癌治疗新靶点奠定理论基础。

T-LAK细胞来源的蛋白激酶（T-LAK cell-originated protein kinase, TOPK）是一种双特异性丝氨酸/苏氨酸激酶，在多种癌症中表达上调并与不良预后相关。Y-box结合蛋白1（Y-box binding protein 1, YB1）是一种DNA/RNA结合蛋白，在多个细胞过程中发挥重要作用。在这里，我们报道了TOPK和YB1均在食管癌（esophageal cancer, EC）中高表达，并与其不良预后有关。敲除TOPK可有效抑制EC细胞增殖，并可通过挽救YB1的表达而逆转。TOPK磷酸化YB1的Thr 89（T89）和Ser 209（S209）氨基酸位点，然后磷酸化的YB1与真核翻译延伸因子1 α1（eukaryotic translation elongation factor 1 alpha 1, eEF1A1）的启动子结合，激活其转录。由此，上调的eEF1A1蛋白激活了AKT/mTOR 信号通路。重要的是，TOPK抑制剂HI-TOPK-032在体内外均可通过TOPK/YB1/eEF1A1信号通路抑制EC的生长。综上所述，我们的研究表明，TOPK和YB1对EC的生长是必不可少的，TOPK抑制剂可能用于重新编码EC的细胞增殖。本研究提示TOPK是EC的一个潜在治疗靶点。