Basic studies on TOPK as a target molecule of cancer

目的：一种类似mapkk的有丝分裂蛋白激酶（TOPK）在癌细胞的生长和运动中起着关键作用。抗HER2单克隆抗体的临床应用证明，EGF-R/HER2通过MAPK-和PI3K-信号介导乳腺癌细胞增殖和侵袭的重要信号。Raf是MAPK信号的重要成员，与TOPK结合，尽管这种相互作用的意义尚未阐明。在本研究中，我们分析了TOPK的表达，并利用乳腺癌细胞研究了TOPK- raf相互作用的生物学意义。实验设计：我们分析TOPK在临床乳腺癌组织中的表达，并从乳腺癌细胞中TOPK和Raf的角度研究mapk信号传导。结果：免疫组化分析显示TOPK的峰值表达强度与乳腺浸润性导管癌的组织学分级相关。我们的研究结果表明，Raf在Thr-198位点磷酸化TOPK， Thr-198是TOPK激酶活性的关键残基，TOPK通过上调Ras与Raf的结合来增强MAPK信号传导。结论：TOPK通过EGF-R/HER2信号通路在乳腺癌的恶性潜能中发挥重要作用。本研究提示TOPK可能成为未来乳腺癌治疗的分子靶点。

Purpose: A MAPKK-like mitotic protein kinase, TOPK, plays a pivotal role in the growth and movement of cancer cells. As is evidenced by clinical application of anti-HER2-monoclonal antibody, EGF-R/HER2 mediates an important signaling in the proliferation and invasion of breast cancer cells through MAPK- and PI3K- signaling. Raf, an imperative member of MAPK signaling, binds to TOPK, although, significance of this interaction has not been elucidated. In this study, we analyzed expression of TOPK and investigated biological significance of TOPK-Raf interaction using breast cancer cells.Experimental Design: We analyzed the expression of TOPK in the clinical breast cancer tissues and investigated MAPK-signaling from the aspect of TOPK and Raf in breast cancer cells.Results: Immunohistochemical analysis revealed that the peak-expression intensity of TOPK correlated with the Histologic Grade of human invasive ductal carcinoma of breast. Our results suggested that Raf phosphorylates TOPK at Thr-198, a critical residue for kinase activity of TOPK and that TOPK enhances MAPK signaling by upregulating Ras binding to Raf.Conclusions: TOPK is indicated to play an important role in the malignant potential of breast cancer via EGF-R/HER2 signaling. This study suggests that TOPK can be a molecular target for breast cancer therapy in the future.