title: Proline-rich tyrosine kinase 2 (Pyk2) promotes cell motility of hepatocellular carcinoma through induction of epithelial to mesenchymal transition.
abstract: OBJECTIVE
  Proline-rich tyrosine kinase 2 (Pyk2), a non-receptor tyrosine kinase of the focal adhesion kinase (FAK) family, is up-regulated in more than 60% of the tumors of hepatocellular carcinoma (HCC) patients. Forced overexpression of Pyk2 can promote the proliferation and invasion of HCC cells. In this study, we aimed to explore the underlying molecular mechanism of Pyk2-mediated cell migration of HCC cells.
  
  
  RESULTS
  We demonstrated that Pyk2 transformed the epithelial HCC cell line Hep3B into a mesenchymal phenotype via the induction of epithelial to mesenchymal transition (EMT), signified by the up-regulation of membrane ruffle formation, activation of Rac/Rho GTPases, down-regulation of epithelial genes E-cadherin and cytokeratin as well as promotion of cell motility in presence of lysophosphatidic acid (LPA). Suppression of Pyk2 by overexpression of dominant negative PRNK domain in the metastatic HCC cell line MHCC97L transformed its fibroblastoid phenotype to an epithelial phenotype with up-regulation of epithelial genes, down-regulation of mesenchymal genes N-cadherin and STAT5b, and reduction of LPA-induced membrane ruffle formation and cell motility. Moreover, overexpression of Pyk2 in Hep3B cells promoted the phosphorylation and localization of mesenchymal gene Hic-5 onto cell membrane while suppression of Pyk2 in MHCC97L cells attenuated its phosphorylation and localization.
  
  
  CONCLUSIONS
  These data provided new evidence of the underlying mechanism of Pyk2 in controlling cell motility of HCC cells through regulation of genes associated with EMT.
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Chris K
authors.initials: CK
authors.lastname: Sun
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Ng
authors.forename: Zophia X
authors.initials: ZX
authors.lastname: Lim
authors.forename: Qiao
authors.initials: Q
authors.lastname: Cheng
authors.forename: Chung Mau
authors.initials: CM
authors.lastname: Lo
authors.forename: Ronnie T
authors.initials: RT
authors.lastname: Poon
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wong
authors.forename: Sheung Tat
authors.initials: ST
authors.lastname: Fan
mesh_terms: D015820:Cadherins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism / Q000502:physiology*; D022001:Focal Adhesions; D006801:Humans; D007633:Keratins / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D008855:Microscopy, Electron, Scanning; D050799:STAT5 Transcription Factor / Q000378:metabolism
chemical_list: D015820:Cadherins; D050799:STAT5 Transcription Factor; D007633:Keratins; D051418:Focal Adhesion Kinase 2