Involvement of protein kinase C β-extracellular signal-regulating kinase_1/2/p38 mitogen-activated protein kinase-heat shock protein 27 activation in hepatocellular carcinoma cell motility and invasion

Authors: Guo, Kun; Liu, Yinkun; Zhou, Haijun; Dai, Zhi; Zhang, Jubo¹; Sun, Ruixia¹; Chen, Jie¹; Sun, Qianglin¹; Lu, Wenjing¹; Kang, Xiaonan; Chen, Pei²

Source: Cancer Science, Volume 99, Number 3, March 2008 , pp. 486-496(11)

Publisher: Wiley-Blackwell

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Abstract:

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 ERK_1/2 and p38 MAPK was regulated by upregulated protein kinase Cβ (PKCβ) in HCC cells through the integrated use of PKCβ RNA interference, the PKCβ 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 PKCβ-ERK_1/2 and PKCβ-p38 MAPK. In vitro migration and invasion assay further showed that the depletion of PKCβ or inhibition of PKCβ activation effectively decreased HCC cell motility and invasion. Moreover, the motility and invasion of phorbol-12-myristate-13-acetate-stimulated PKCβ-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 PKCβ-mediated HCC cell motility and invasion. Taken together, this study reveals the important role of this PKCβ-ERK_1/2/p38MAPK-HSP27 pathway, which was verified for the first time, in modulating HCC cell motility and invasion. (Cancer Sci 2008; 99: 486-496)

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1349-7006.2007.00702.x

Affiliations: 1: Liver Cancer Institute, Zhongshan Hospital, and 2: Research Center for Cancer, Institute of Biomedical Science, Fudan University, No.180, Fenglin Road, Shanghai 200032, China

Publication date: 2008-03-01