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p38 Mitogen-Activated Protein Kinase Pathway Is Involved in Protein Kinase C–Regulated Invasion in Human Hepatocellular Carcinoma Cells

¹ Institute of Biochemistry and Biotechnology and ² Department of Surgery, School of Medicine, College of Medicine, Chung Shan Medical University, ³ Graduate Institute of Chinese Medical Science, School of Chinese Medicine, China Medical University, and ⁴ School of Applied Chemistry, Health Care and Management College, Chung Shan Medical University, Taichung, Taiwan, Republic of China

Requests for reprints: Jer-Yuh Liu, Institute of Biochemistry and Biotechnology, Medical College, Chung Shan Medical University, No. 110, Sec. 1, Chien Kou N. Road, Taichung 402, Taiwan, Republic of China. Phone: 886-4-24730022 ext. 11673; Fax: 886-4-23248195; E-mail: jyl{at}csmu.edu.tw.

Protein kinase C (PKC) has been suggested to play an important role in tumorigenesis, invasion, and metastasis. In this study, we investigated the signal pathways selectively activated by PKC in human hepatocellular carcinoma (HCC) cells to determine the role of mitogen-activated protein kinases (MAPK) in PKC-mediated HCC migration and invasion. A stable SK-Hep-1 cell clone (siPKC-SK) expressing DNA-based small interfering RNA (siRNA) PKC was established and was then characterized by cell growth, migration, and invasion. The expression of PKC was decreased in siPKC-SK, and cell growth, migration, and invasion were reduced. These changes were associated with the decrease in p38 MAPK phosphorylation level, but not in c-jun-NH₂-kinase-1/2 (JNK-1/2) and extracellular signal-regulated kinase-1/2 (ERK-1/2). This phenomenon was confirmed in the SK-Hep-1 cells treated with antisense PKC olignucleotide. The p38 MAPK inhibitor SB203580 or dominant negative p38 mutant plasmid (DN-p38) was used to evaluate the dependency of p38 MAPK in PKC-regulated migration and invasion. Attenuation of cell migration and invasion was revealed in the SK-Hep-1 cells treated with the SB203580 or DN-p38, but not with ERK-1/2 inhibitor PD98059 or JNK-1/2 inhibitor SP600125. Overexpression of constitutively active MKK6 or PKC may restore the inactivation of p38 and the attenuation of cell migration and invasion in siPKC-SK. Similar findings were observed in the stable HA22T/VGH cell clone expressing siRNA PKC. This study provides new insight into the role of p38 MAPK in PKC-mediated malignant phenotypes, especially in PKC-mediated cancer cell invasion, which may have valuable implications for developing new therapies for some PKC-overexpressing cancers. [Cancer Res 2007;67(9):4320–7]

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