Basic studies on TOPK as a target molecule of cancer

目的：一种MAPKK样有丝分裂蛋白激酶TOPK在癌细胞的生长和运动中起着关键作用。抗HER2单抗的临床应用证明，EGF-R/HER2通过MAPK和PI3K信号通路在乳腺癌细胞的增殖和侵袭中发挥重要作用。RAF是MAPK信号通路中的重要成员，它与TOPK结合，但这种相互作用的意义尚未阐明。实验设计：分析TOPK在临床乳腺癌组织中的表达，并从TOPK和Raf的角度探讨乳腺癌细胞中MAPK信号转导途径。结果：免疫组织化学分析结果显示，TOPK的峰值表达强度与乳腺浸润性导管癌的组织学分级有关。我们的结果提示，RAF通过上调RAS与RAF的结合，使TOPK在Thr-198处磷酸化，而TOPK通过上调RAS与RAF的结合来增强MAPK信号。结论：TOPK可能通过EGF-R/HER2信号通路在乳腺癌的恶性潜能中发挥重要作用。这项研究表明，TOPK可以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.