The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
The Hormel Institute, University of Minnesota, Austin, MN 55912, USA; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China.
EBioMedicine. 2017 Apr;18:73-82. doi: 10.1016/j.ebiom.2017.04.003. Epub 2017 Apr 6.
Approximately 90% of all cancer deaths arise from the metastatic dissemination of primary tumors. Metastasis is the most lethal attribute of colorectal cancer. New data regarding the molecules contributing to the metastatic phenotype, the pathways they control and the genes they regulate are very important for understanding the processes of metastasis prognosis and prevention in the clinic. The purpose of this study was to investigate the role of T-LAK cell-originated protein kinase (TOPK) in the promotion of colorectal cancer metastasis. TOPK is highly expressed in human metastatic colorectal cancer tissue compared with malignant adenocarcinoma. We identified p53-related protein kinase (PRPK) as a new substrate of TOPK. TOPK binds with and phosphorylates PRPK at Ser250 in vitro and ex vivo. This site plays a critical role in the function of PRPK. Cell lines stably expressing mutant PRPK (S250A), knockdown TOPK, knockdown PRPK or knockdown of both TOPK and PRPK significantly inhibited liver metastasis of human HCT116 colon cancer cells in a xenograft mouse model. Therefore, we conclude that TOPK directly promotes metastasis of colorectal cancer by modulating PRPK. Thus, these findings may assist in the prediction of prognosis or development of new therapeutic strategies against colon cancer.
约 90%的癌症死亡是由原发性肿瘤的转移扩散引起的。转移是结直肠癌最致命的特征。关于有助于转移表型的分子、它们控制的途径以及它们调节的基因的新数据，对于理解临床转移预后和预防过程非常重要。本研究旨在探讨 T-LAK 细胞起源蛋白激酶 (TOPK) 在促进结直肠癌转移中的作用。与恶性腺癌相比，TOPK 在人转移性结直肠癌组织中高度表达。我们确定 p53 相关蛋白激酶 (PRPK) 是 TOPK 的一个新底物。TOPK 在体外和体内与 PRPK 结合并在 Ser250 处磷酸化 PRPK。该位点在 PRPK 的功能中起着关键作用。稳定表达突变型 PRPK (S250A)、敲低 TOPK、敲低 PRPK 或同时敲低 TOPK 和 PRPK 的细胞系显著抑制了异种移植小鼠模型中人 HCT116 结肠癌细胞的肝转移。因此，我们得出结论，TOPK 通过调节 PRPK 直接促进结直肠癌的转移。因此，这些发现可能有助于预测结直肠癌的预后或开发新的治疗策略。
