Key Laboratory of Systems Biomedicine (Ministry of Education) of Rui-Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Mol Cell Biochem. 2013 Jul;379(1-2):191-9. doi: 10.1007/s11010-013-1641-7. Epub 2013 May 6.
Protein kinases are important regulators in biologic processes. Aberrant expression of protein kinases often causes diseases including cancer. In the present study, we found that the serine-arginine protein kinase 1 (SRPK1) might be involved in hepatocellular carcinoma (HCC) proliferation from a kinome screen using a loss-of-function approach. In clinical samples, SRPK1 was frequently up-regulated in HCCs as compared with adjacent non-tumor tissues at both mRNA and protein levels. Functional studies indicated that overexpression of wild-type SRPK1 promoted HCC cell proliferation, while forced expression of the kinase-dead mutant of SRPK1 or RNA interference against SRPK1 suppressed cell growth and malignancy as measured in soft agar assay. The kinase-dead mutant of SRPK1 also inhibited subcutaneous xenografts' growth of HCC cells in nude mice. Furthermore, western bolt analysis showed overexpression of wild-type SRPK1 enhanced Akt phosphorylation and knockdown of SRPK1 by RNA interference attenuated Akt phosphorylation induced by epidermal growth factor. Meanwhile, overexpression of wild-type SRPK1 also induced a concurrent increase in the total tyrosine phosphorylation of phosphotidylinositol-3 kinase p110α subunit, indicating a functional link between SRPK1 and PI3K/Akt signaling. Our findings suggest that SRPK1 plays an oncogenic role and could be a potential therapeutic target in HCC.
蛋白激酶是生物过程中的重要调节因子。蛋白激酶的异常表达常导致包括癌症在内的多种疾病。本研究通过功能丧失筛选方法，在激酶组中发现丝氨酸-精氨酸蛋白激酶 1（SRPK1）可能参与肝癌（HCC）的增殖。在临床样本中，与相邻非肿瘤组织相比，SRPK1 在 HCC 中无论是在 mRNA 水平还是蛋白水平均呈高频上调。功能研究表明，野生型 SRPK1 的过表达促进 HCC 细胞增殖，而 SRPK1 的激酶失活突变的强制表达或针对 SRPK1 的 RNA 干扰则抑制了软琼脂测定中细胞生长和恶性程度。SRPK1 的激酶失活突变也抑制了裸鼠中 HCC 细胞皮下异种移植物的生长。此外，western bolt 分析表明，野生型 SRPK1 的过表达增强了 Akt 磷酸化，而 RNA 干扰对 SRPK1 的敲低减弱了表皮生长因子诱导的 Akt 磷酸化。同时，野生型 SRPK1 的过表达也导致磷酯酰肌醇-3 激酶 p110α 亚基的总酪氨酸磷酸化的同时增加，表明 SRPK1 与 PI3K/Akt 信号之间存在功能联系。我们的研究结果表明，SRPK1 发挥致癌作用，可能是 HCC 的潜在治疗靶点。
