Involvement of protein kinase C β-extracellular signal-regulating kinase1/2/p38 mitogen-activated protein kinase-heat shock protein 27 activation in hepatocellular carcinoma cell motility and invasion
Involvement of protein kinase C β-extracellular signal-regulating kinase1/2/p38 mitogen-activated protein kinase-heat shock protein 27 activation in hepatocellular carcinoma cell motility and invasion
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DOI：
10.1111/j.1349-7006.2007.00702.x
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发表时间：
2008-03-01
期刊：
影响因子：
5.7
通讯作者：
Chen, Pei
中科院分区：
文献类型：
--
作者：
Guo, Kun;Liu, Yinkun;Chen, Pei
为了了解各种重要信号通路在肝细胞癌（HCC）转移中作用的分子机制，在培养的具有自发转移潜力增加的HCC细胞模型（MHCC97L、MHCC97H和HCCLM6）中进行了人信号转导寡核苷酸微阵列分析。结果显示，丝裂原活化蛋白激酶（MAPK）通路是HCC转移中显著上调的通路。进一步研究表明，从MHCC97L到MHCC97H再到HCCLM6细胞，细胞外信号调节激酶（ERK）（1/2）和p38 MAPK的基础磷酸化水平依次升高，但c-Jun n -末端激酶没有。在HCC细胞中，ERK1/2和p38 MAPK的磷酸化通过PKC β RNA干扰、PKC β特异性抑制剂enzastaurin和PKC激活剂phorol -12-肉肉酸酯-13-醋酸酯的综合使用，受到PKC β上调的蛋白激酶C β (PKC β)的调控。热休克蛋白27 （HSP27）也被证实是PKC β - erk1 /2和PKC β -p38 MAPK的下游共同活化蛋白。体外迁移和侵袭实验进一步表明，PKC β的缺失或PKC β活化的抑制有效地降低了HCC细胞的运动和侵袭。此外，ERK抑制剂1.4-二氨基-2.3-二氨基-1.4-双[2-氨基苯基]丁二烯或p38 MAPK抑制剂4-（4-氟苯基）-2-（4-甲基亚砜基苯基）-5-（4-吡啶基）1h -咪唑显著地抑制了苯酚-12-豆芽糖酸-13-乙酸酯刺激的PKC β介导的HCC细胞的活力和侵袭。它还表明HSP27在PKC β介导的HCC细胞运动和侵袭中起关键作用。综上所述，本研究首次证实了PKC β - erk1 /2/p38MAPK-HSP27通路在调节HCC细胞运动和侵袭中的重要作用。
To understand the molecular mechanism that underlies the role of various prominent signal pathways in hepatocellular carcinoma (HCC) metastasis, a human signal transduction oligonucleotide microarray analysis was carried out in cultured HCC cell models with increasing spontaneous metastatic potential (MHCC97L, MHCC97H, and HCCLM6). The results revealed that the mitogen-activated protein kinase (MAPK) pathway is the prominently upregulated pathway in HCC metastasis. Further study showed that basal phosphorylated levels of extracellular signal-regulating kinase (ERK)(1/2) and p38 MAPK consecutively increased from MHCC97L to MHCC97H to HCCLM6 cells, but not c-Jun N-terminal kinase. The phosphorylation of ERK1/2 and p38 MAPK was regulated by upregulated protein kinase C beta (PKC beta) in HCC cells through the integrated use of PKC beta RNA interference, the PKC beta specific inhibitor enzastaurin and a PKC activator phorbol-12-myristate-13-acetate. Heat shock protein 27 (HSP27) was also verified as a downstream common activated protein of PKC beta-ERK1/2 and PKC beta-p38 MAPK. In vitro migration and invasion assay further showed that the depletion of PKC beta or inhibition of PKC beta activation effectively decreased HCC cell motility and invasion. Moreover, the motility and invasion of phorbol-12-myristate-13-acetate-stimulated PKC beta-mediated HCC cells was significantly negated by an ERK inhibitor, 1.4-diamino-2.3-dicyano-1.4-bis[2-aminophenylthio] butadiene, or a p38 MAPK inhibitor, 4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole. It also showed that HSP27 is critical in PKC beta-mediated HCC cell motility and invasion. Taken together, this study reveals the important role of this PKC beta-ERK1/2/p38MAPK-HSP27 pathway, which was verified for the first time, in modulating HCC cell motility and invasion.