title: The role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in hepatocellular carcinoma.
abstract: OBJECTIVE
  We previously demonstrated Proline rich tyrosine kinase 2 (Pyk2) plays important roles in regulating tumor progression, migration and invasion in hepatocellular carcinoma (HCC). In this study, we aimed to examine the role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in HCC and to explore its underlying molecular mechanism.
  
  
  RESULTS
  Stable transfectants either overexpressing or suppressing Pyk2 were established in different HCC cell lines. MTT, colony formation and Annexin-V assays were employed to examine their in vitro responses to cisplatin. Xenograft ectopic and orthotopic nude mice models were generated to investigate the in vivo responses of them to cisplatin treatment. cDNA microarray was performed to identify Pyk2-induced genes which were further validated by quantitative real-time RT-PCR using clinical HCC samples. In vitro functional study demonstrated that Pyk2-overexpressing HCC transfectants exhibited relatively lower cytotoxicity, higher colony-forming ability and lower apoptosis to cisplatin compared with the control transfectants. Moreover, Pyk2 overexpressing HCC transfectants had a higher survival rate under cisplatin treatment by up-regulation of AKT phosphorylation. In vivo xenograft nude mice model demonstrated that Pyk2-overexpressing transfectants developed higher tolerance to cisplatin treatment together with less tumor necrosis and apoptosis. cDNA microarray analysis revealed that there were more than 4,000 genes differentially expressed upon overexpression of Pyk2. Several upregulated genes were found to be involved in drug resistance and invasion in cancers. Among them, the expression profiles of MDR1, GAGE1, STAT1 and MAP7 were significantly associated with the expression of Pyk2 in clinical HCC samples.
  
  
  CONCLUSIONS
  Our results may suggest a new evidence of Pyk2 on promoting cisplatin resistance of HCC cells through preventing cell apoptosis, activation of AKT pathway and upregulation of drug resistant genes.
authors.affiliation: Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Geng
authors.forename: Kevin T P
authors.initials: KT
authors.lastname: Ng
authors.forename: Chris K W
authors.initials: CK
authors.lastname: Sun
authors.forename: Wing Lung
authors.initials: WL
authors.lastname: Yau
authors.forename: Xiao Bing
authors.initials: XB
authors.lastname: Liu
authors.forename: Qiao
authors.initials: Q
authors.lastname: Cheng
authors.forename: Ronnie T P
authors.initials: RT
authors.lastname: Poon
authors.forename: Chung Mau
authors.initials: CM
authors.lastname: Lo
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
authors.forename: Sheung Tat
authors.initials: ST
authors.lastname: Fan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D051418:Focal Adhesion Kinase 2; D002945:Cisplatin
references.citation: Cancer Metastasis Rev. 2009 Jun;28(1-2):35-49
references.pmid: 19169797
references.citation: PLoS One. 2011 Apr 20;6(4):e18878
references.pmid: 21533080
references.citation: Nat Cell Biol. 2000 May;2(5):249-56
references.pmid: 10806474
references.citation: Mol Cell Endocrinol. 2002 Jan 15;186(1):81-7
references.pmid: 11850124
references.citation: Carcinogenesis. 2008 Nov;29(11):2096-105
references.pmid: 18765415
references.citation: Eur J Surg Oncol. 2009 Feb;35(2):174-9
references.pmid: 18325724
references.citation: Cancer Res. 1975 Dec;35(12):3698-704
references.pmid: 1192428
references.citation: Cell Mol Life Sci. 2010 Nov;67(22):3893-903
references.pmid: 20521079
references.citation: J Biol Chem. 1995 Sep 8;270(36):21206-19
references.pmid: 7673154
references.citation: Oncogene. 2003 Oct 20;22(47):7265-79
references.pmid: 14576837
references.citation: N Engl J Med. 2008 Jul 24;359(4):378-90
references.pmid: 18650514
references.citation: World J Surg Oncol. 2011 May 03;9:46
references.pmid: 21539750
references.citation: Clin Cancer Res. 2010 Feb 1;16(3):967-77
references.pmid: 20103676
references.citation: J Neurosurg Pediatr. 2008 Apr;1(4):305-13
references.pmid: 18377306
references.citation: Cancer Lett. 2009 Dec 1;286(1):114-20
references.pmid: 19664880
references.citation: Histol Histopathol. 2009 Apr;24(4):503-10
references.pmid: 19224453
references.citation: Cancer Res. 2007 Jul 1;67(13):6325-32
references.pmid: 17616691
references.citation: Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18490-5
references.pmid: 19001271
references.citation: Oncologist. 2009 Jan;14(1):95-100
references.pmid: 19144678
references.citation: Am J Pathol. 2008 Nov;173(5):1540-50
references.pmid: 18832579
references.citation: Cancer Immun. 2002 Sep 19;2:11
references.pmid: 12747756
references.citation: Cancer Res. 2005 Sep 15;65(18):8423-32
references.pmid: 16166321
references.citation: Oncogene. 2000 Mar 2;19(10):1318-28
references.pmid: 10713673
references.citation: Biochim Biophys Acta. 2005 Sep 30;1745(3):401-10
references.pmid: 16054712
references.citation: Br J Cancer. 2007 Jul 2;97(1):50-7
references.pmid: 17551499
references.citation: Lab Invest. 2001 Jan;81(1):51-9
references.pmid: 11204274
references.citation: Cancer Res. 2008 Sep 15;68(18):7613-20
references.pmid: 18794150
references.citation: Respiration. 2009;78(1):49-55
references.pmid: 18812689
references.citation: Cell Signal. 2000 Mar;12(3):123-33
references.pmid: 10704819
references.citation: Nat Rev Gastroenterol Hepatol. 2009 Jul;6(7):423-32
references.pmid: 19488072
references.citation: Liver Int. 2009 Jan;29(1):10-7
references.pmid: 19120940
references.citation: J Hepatol. 2004 Jul;41(1):104-11
references.pmid: 15246215
references.citation: Ann Surg. 2010 Jun;251(6):1154-61
references.pmid: 20485145
references.citation: Gastroenterology. 2007 Jun;132(7):2557-76
references.pmid: 17570226
references.citation: Cancer Biol Ther. 2009 May;8(9):856-65
references.pmid: 19458500
references.citation: Biochem Biophys Res Commun. 2010 Apr 9;394(3):600-5
references.pmid: 20214883
references.citation: J Gastroenterol. 2009;44 Suppl 19:136-41
references.pmid: 19148808
references.citation: Am J Transplant. 2005 Jan;5(1):40-9
references.pmid: 15636610
references.citation: Mol Pharmacol. 2001 Apr;59(4):657-63
references.pmid: 11259608
references.citation: Gan To Kagaku Ryoho. 2004 Dec;31(13):2122-8
references.pmid: 15628756
references.citation: Int J Oncol. 2010 Jul;37(1):89-96
references.pmid: 20514400
references.citation: Verh Dtsch Ges Pathol. 2004;88:207-13
references.pmid: 16892554
references.citation: Clin Cancer Res. 2005 Dec 1;11(23):8458-66
references.pmid: 16322309
references.citation: Nat Rev Cancer. 2005 Jul;5(7):505-15
references.pmid: 16069815
references.citation: J Gastroenterol Hepatol. 2001 Apr;16(4):460-6
references.pmid: 11354286
references.citation: Int J Oncol. 1999 Sep;15(3):559-63
references.pmid: 10427140
references.citation: Clin Cancer Res. 2009 May 15;15(10):3462-71
references.pmid: 19447872
references.citation: J Gastroenterol Hepatol. 1997 Aug;12(8):569-75
references.pmid: 9304508
references.citation: Lung Cancer. 2008 Dec;62(3):295-301
references.pmid: 18571765
references.citation: Hepatology. 2008 Dec;48(6):2047-63
references.pmid: 19003900