Phosphorylated Heat Shock Protein 20 (HSPB6) Regulates Transforming Growth Factor-α-Induced Migration and Invasion of Hepatocellular Carcinoma Cells.
Phosphorylated Heat Shock Protein 20 (HSPB6) Regulates Transforming Growth Factor-α-Induced Migration and Invasion of Hepatocellular Carcinoma Cells.
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DOI：
10.1371/journal.pone.0151907
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Kozawa O
中科院分区：
文献类型：
--
作者：
Matsushima-Nishiwaki R;Toyoda H;Nagasawa T;Yasuda E;Chiba N;Okuda S;Maeda A;Kaneoka Y;Kumada T;Kozawa O
人类肝细胞癌（HCC）是世界上主要的恶性肿瘤之一。据报道，小热休克蛋白（HSPs）在多种癌细胞功能的调节中发挥重要作用，小热休克蛋白的功能通过磷酸化等翻译后修饰来调节。我们之前报道了小热休克蛋白HSP20 （HSPB6）在血管浸润阳性HCC中的蛋白水平比血管浸润阴性HCC中的蛋白水平降低。因此，在本研究中，我们使用人HCC来源的HuH7细胞来研究HSP20是否与HCC细胞的迁移和侵袭有关。在检测到HSP20磷酸化的野生型HSP20过表达细胞中，转化生长因子(TGF)-α-诱导的迁移和侵袭受到抑制。与未磷酸化的HSP20过表达相比，磷酸化-模拟HSP20过表达减少了迁移和侵袭。二丁基cAMP增强了野生型HSP20的磷酸化，显著降低了TGF-α-诱导的野生型HSP20过表达细胞的细胞迁移。c-Jun n -末端激酶（JNK）抑制剂SP600125可抑制TGF-α-诱导的细胞迁移。在磷酸化模拟HSP20过表达的HuH7细胞中，与未磷酸化的HSP20过表达细胞相比，TGF-α-刺激的JNK磷酸化被抑制。此外，人HCC组织中phospho-HSP20蛋白水平与肿瘤侵袭有显著相关性。综上所述，我们的研究结果强烈提示磷酸化的HSP20通过抑制JNK信号通路抑制TGF-α-诱导的HCC细胞迁移和侵袭。
Human hepatocellular carcinoma (HCC) is one of the major malignancies in the world. Small heat shock proteins (HSPs) are reported to play an important role in the regulation of a variety of cancer cell functions, and the functions of small HSPs are regulated by post-translational modifications such as phosphorylation. We previously reported that protein levels of a small HSP, HSP20 (HSPB6), decrease in vascular invasion positive HCC compared with those in the negative vascular invasion. Therefore, in the present study, we investigated whether HSP20 is implicated in HCC cell migration and the invasion using human HCC-derived HuH7 cells. The transforming growth factor (TGF)-α-induced migration and invasion were suppressed in the wild-type-HSP20 overexpressed cells in which phosphorylated HSP20 was detected. Phospho-mimic-HSP20 overexpression reduced the migration and invasion compared with unphosphorylated HSP20 overexpression. Dibutyryl cAMP, which enhanced the phosphorylation of wild-type-HSP20, significantly reduced the TGF-α-induced cell migration of wild-type HSP20 overexpressed cells. The TGF-α-induced cell migration was inhibited by SP600125, a c-Jun N-terminal kinases (JNK) inhibitor. In phospho-mimic-HSP20 overexpressed HuH7 cells, TGF-α-stimulated JNK phosphorylation was suppressed compared with the unphosphorylated HSP20 overexpressed cells. Moreover, the level of phospho-HSP20 protein in human HCC tissues was significantly correlated with tumor invasion. Taken together, our findings strongly suggest that phosphorylated HSP20 inhibits TGF-α-induced HCC cell migration and invasion via suppression of the JNK signaling pathway.