title: High expression of proline-rich tyrosine kinase 2 is associated with poor survival of hepatocellular carcinoma via regulating phosphatidylinositol 3-kinase/AKT pathway.
abstract: BACKGROUND
  The peritumoral environment has been implicated to be important in the process of metastasis and recurrence in hepatocellular carcinoma (HCC). Our aims were to assess the prognostic value of proline-rich tyrosine kinase 2 (Pyk2) in HCC and investigate related molecular mechanism.
  
  
  METHODS
  Expression of Pyk2 was tested by immunohistochemistry in tissue microarrays containing 141 paired HCC samples. Correlation between Pyk2 and vascular endothelial growth factor (VEGF) expression in clinical samples was analyzed by Spearman rank correlation. Matrigel invasion, anchorage-independent growth assay and immunoblotting were performed to study the effect of Pyk2 on the invasion and progression of HCC cells and phosphoinositide 3-kinase (PI3K)/AKT pathway activation.
  
  
  RESULTS
  Higher Pyk2 density in both tumor and peritumor was associated with lower overall survival (P = 0.044; P = 0.041, respectively), serum AFP levels > 1,000 ng/ml (P = 0.013; P = 0.032, respectively) and postoperative distant metastasis (both P < 0.001). However, only higher peritumoral Pyk2 density was related to lower disease-free survival (P = 0.014) and vascular invasion (P = 0.035). A significant correlation between Pyk2 and VEGF density in tumor or peritumoral liver tissue was observed (r = 0. 3133, P = 0.0002; r = 0.5176, P < 0.0001, respectively). Immunoblotting showed that Pyk2 activated PI3K-AKT pathway to upregulate VEGF expression in HL-7702, SMMC-7721 and HepG2 cells.
  
  
  CONCLUSIONS
  High Pyk2, especially peritumoral Pyk2 was associated with poor survival, disease recurrence, and metastasis in HCC. PI3K-AKT pathway was involved in Pyk2-mediated VEGF expression during HCC progression and invasion.
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Cao
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Fu
authors.forename: You-Wen
authors.initials: YW
authors.lastname: Qian
authors.forename: Yi-Bin
authors.initials: YB
authors.lastname: Ren
authors.forename: Bo
authors.initials: B
authors.lastname: Su
authors.forename: Tao
authors.initials: T
authors.lastname: Luo
authors.forename: Rong-Yang
authors.initials: RY
authors.lastname: Dai
authors.forename: Liang
authors.initials: L
authors.lastname: Huang
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Yan
authors.forename: Meng-Chao
authors.initials: MC
authors.lastname: Wu
authors.forename: Yi-Qun
authors.initials: YQ
authors.lastname: Yan
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Wang
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000401:mortality* / Q000556:secondary; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology / Q000401:mortality* / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D058539:Phosphatidylinositol 3-Kinase; D051418:Focal Adhesion Kinase 2; D051057:Proto-Oncogene Proteins c-akt