Carcinogenesis Advance Access published online on September 1, 2008
Carcinogenesis, doi:10.1093/carcin/bgn203
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Proline-rich tyrosine kinase2 (Pyk2) promotes proliferation and invasiveness of hepatocellular carcinoma cells through c-Src/ERK activation
Department of Surgery and Centre for Cancer Research , The University of Hong Kong, Pokfulam, Hong Kong, China
To whom correspondence should be addressed at: Dr K Man or Prof RT Poon, Department of Surgery and Centre for Cancer Research, The University of Hong Kong, L9-55, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong, China Tel: 852 28199646 Fax: 852 28199634 E-mail: kwanman{at}hkucc.hku.hk or poontp{at}hkucc.hku.hk
The aim of the current study is to elucidate the mechanism of Pyk2 mediated cell proliferation and invasiveness in hepatocellular carcinoma (HCC) cells. Human HCC cell lines PLC and MHCC97L were stably transfected with either full length Pyk2 or C-terminal of Pyk2 (PRNK). Functional studies on cell proliferation and invasion were conducted in vitro by colony formation assay, adhesion assay, migration assay and wound healing assay. For the in vivo study, an orthotopic nude mice liver tumor model was applied to investigate the effects of Pyk2 over-expression on tumor growth and metastasis. Over-expression of Pyk2 in PLC cells resulted in an up-regulation of colony formation (P=0.021) and adhesion towards laminin (P=0.018). Pyk2 promoted wound recovery by stimulation of actin stress fibers polymerization. In the in vivo study, transfection of PRNK in MHCC97L cells significantly decreased tumor volume (P=0.001) and the incidence of lung metastasis (P=0.014). Over-expression of Pyk2 promoted the activation of c-Src, formation of Pyk2/c-Src complex, and activated the ERK/MAPK signaling pathway. Pyk2 up-regulated the activation of ERK1/2 which is insensitive to MEK1/2 inhibition. On the contrary, PRNK over-expression down-regulated the activation of c-Src and ERK/MAPK signaling pathways. Immunofluorescence staining showed that the focal adhesion localization of Pyk2 is a major determinant for c-Src and ERK/MAPK activation. In conclusion, our results showed that Pyk2 promoted cell proliferation and invasiveness by up-regulation of the c-Src and ERK/MAPK signaling pathways.
Key Words: hepatocellular carcinoma (HCC) • proliferation and invasion • proline-rich tyrosine kinase2 (Pyk2) • orthotopic liver tumor nude mice model
Received April 26, 2008; revised July 29, 2008; accepted August 23, 2008.
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