STK39 is a novel kinase contributing to the progression of hepatocellular carcinoma by the PLK1/ERK signaling pathway.
STK39 is a novel kinase contributing to the progression of hepatocellular carcinoma by the PLK1/ERK signaling pathway.
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作者：
Zhang C;Wang X;Fang D;Xu P;Mo X;Hu C;Abdelatty A;Wang M;Xu H;Sun Q;Zhou G;She J;Xia J;Hui KM;Xia H
原理：蛋白激酶是治疗肝细胞癌（HCC）的关键治疗靶点。丝氨酸/苏氨酸激酶39（serine/threonine kinase 39，STK 39）作为一种丝氨酸/苏氨酸激酶，其在肝癌中的作用尚待进一步研究。方法：采用RT-qPCR、Western blotting和免疫组织化学方法检测STK 39的表达。CCK 8和TUNEL试剂盒检测细胞增殖和凋亡。使用具有或不具有Matrigel的transwell系统进行细胞迁移和侵袭测定。使用RNA-seq、质谱和荧光素酶报告基因测定来鉴定STK 39结合蛋白。结果如下：本研究首次报道STK 39在临床肝癌组织中的高表达，STK 39的高表达是由转录因子SP1诱导的，与患者的生存率相关。功能获得和丧失分析显示STK 39的过表达促进HCC细胞增殖、迁移和侵袭。相反，STK 39的缺失减弱了HCC细胞的生长和转移。STK 39基因的敲除可使肝癌细胞周期阻滞于G2/M期，并促进细胞凋亡。在机制研究中，RNA-seq揭示STK 39正调控ERK信号通路。质谱鉴定STK 39与PLK 1结合，STK 39促进HCC进展并激活依赖于PLK 1的ERK信号通路。结论：因此，我们的研究揭示了STK 39/PLK 1/ERK信号轴在HCC发生发展中的新作用，提示STK 39可作为HCC预后的指标和潜在的药物靶点。
Rationale: Protein kinases are critical therapeutic targets for curing hepatocellular carcinoma (HCC). As a serine/threonine kinase, the potential roles of serine/threonine kinase 39 (STK39) in HCC remain to be explored. Methods: The expression of STK39 was examined by RT-qPCR, western blotting and immunohistochemistry. Cell proliferation and apoptosis were detected by CCK8 and TUNEL kit. Cell migration and invasion assays were performed using a transwell system with or without Matrigel. RNA-seq, mass spectrometry and luciferase reporter assays were used to identify STK39 binding proteins. Results: Here, we firstly report that STK39 was highly overexpressed in clinical HCC tissues compared with adjacent tissues, high expression of STK39 was induced by transcription factor SP1 and correlated with poor patient survival. Gain and loss of function assays revealed that overexpression of STK39 promoted HCC cell proliferation, migration and invasion. In contrast, the depletion of STK39 attenuated the growth and metastasis of HCC cells. Moreover, knockdown of STK39 induced the HCC cell cycle arrested in the G2/M phase and promoted apoptosis. In mechanistic studies, RNA-seq revealed that STK39 positively regulated the ERK signaling pathway. Mass spectrometry identified that STK39 bound to PLK1 and STK39 promoted HCC progression and activated ERK signaling pathway dependent on PLK1. Conclusions: Thus, our study uncovers a novel role of STK39/PLK1/ERK signaling axis in the progress of HCC and suggests STK39 as an indicator for prognosis and a potential drug target of HCC.
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