associated with both mesenchymal and epithelial transformations. Targeting of Pyk2 should be a promising therapeutic strategy to reduce HCC metastasis. References 1. Farazi PA, DePinho RA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6: 674–687. 2. Mathurin P, Rixe O, Carbonell N, Bernard B, Cluzel P, et al. (1998) Review article: Overview of medical treatments in unresectable hepatocellular carcinoma–an impossible meta-analysis? Aliment Pharmacol Ther 12: 111–126. 3. Kawano Y, Sasaki A, Kai S, Endo Y, Iwaki K, et al. (2008) Prognosis of patients with intrahepatic recurrence after hepatic resection for hepatocellular carcino- ma: A retrospective study. Eur J Surg Oncol. 4. Liotta LA (1985) Mechanisms of cancer invasion and metastasis. Important Adv Oncol. pp 28–41. 5. Stracke ML, Liotta LA (1992) Multi-step cascade of tumor cell metastasis. In Vivo 6: 309–316. 6. Larue L, Bellacosa A (2005) Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 39 kinase/AKT pathways. Oncogene 24: 7443–7454. 7. Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442–454. 8. Moustakas A, Heldin CH (2007) Signaling networks guiding epithelial- mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci 98: 1512–1520. 9. Chaffer CL, Brennan JP, Slavin JL, Blick T, Thompson EW, et al. (2006) Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res 66: 11271–11278. 10. Huber MA, Kraut N, Beug H (2005) Molecular requirements for epithelial- mesenchymal transition during tumor progression. Curr Opin Cell Biol 17: 548–558. 11. Boivin D, Bilodeau D, Beliveau R (1996) Regulation of cytoskeletal functions by Rho small GTP-binding proteins in normal and cancer cells. Can J Physiol Pharmacol 74: 801–810. 12. Niu RF, Zhang L, Xi GM, Wei XY, Yang Y, et al. (2007) Up-regulation of Twist induces angiogenesis and correlates with metastasis in hepatocellular carcinoma. J Exp Clin Cancer Res 26: 385–394. 13. Teng Y, Zeisberg M, Kalluri R (2007) Transcriptional regulation of epithelial- mesenchymal transition. J Clin Invest 117: 304–306. 14. Sun CK, Ng KT, Sun BS, Ho JW, Lee TK, et al. (2007) The significance of proline-rich tyrosine kinase2 (Pyk2) on hepatocellular carcinoma progression and recurrence. Br J Cancer 97: 50–57. 15. Sun CK, Man K, Ng KT, Ho JW, Lim ZX, et al. (2008) Proline-rich tyrosine kinase 2 (Pyk2) promotes proliferation and invasiveness of hepatocellular carcinoma cells through c-Src/ERK activation. Carcinogenesis 29: 2096–2105. 16. Lee TK, Man K, Poon RT, Lo CM, Yuen AP, et al. (2006) Signal transducers and activators of transcription 5b activation enhances hepatocellular carcinoma aggressiveness through induction of epithelial-mesenchymal transition. Cancer Res 66: 9948–9956. 17. Avraamides C, Bromberg ME, Gaughan JP, Thomas SM, Tsygankov AY, et al. (2007) Hic-5 promotes endothelial cell migration to lysophosphatidic acid. Am J Physiol Heart Circ Physiol 293: H193–203. 18. Shibanuma M, Mashimo J, Kuroki T, Nose K (1994) Characterization of the TGF beta 1-inducible hic-5 gene that encodes a putative novel zinc finger protein and its possible involvement in cellular senescence. J Biol Chem 269: 26767–26774. Pyk2 on Cell Motility of Hepatocellular Carcinoma Author Contributions Conceived and designed the experiments: CKS KTN KM. Performed the experiments: CKS KTN ZXL QC. Analyzed the data: CKS KTN KM NW. Contributed reagents/materials/analysis tools: RTP CML STF. Wrote the paper: CKS KTN. 19. Brown MC, Curtis MS, Turner CE (1998) Paxillin LD motifs may define a new family of protein recognition domains. Nat Struct Biol 5: 677–678. 20. Tumbarello DA, Brown MC, Hetey SE, Turner CE (2005) Regulation of paxillin family members during epithelial-mesenchymal transformation: a putative role for paxillin delta. J Cell Sci 118: 4849–4863. 21. Nishiya N, Sabe H, Nose K, Shibanuma M (1998) The LIM domains of hic-5 protein recognize specific DNA fragments in a zinc-dependent manner in vitro. Nucleic Acids Res 26: 4267–4273. 22. Matsuya M, Sasaki H, Aoto H, Mitaka T, Nagura K, et al. (1998) Cell adhesion kinase beta forms a complex with a new member, Hic-5, of proteins localized at focal adhesions. J Biol Chem 273: 1003–1014. 23. Ishino M, Aoto H, Sasaski H, Suzuki R, Sasaki T (2000) Phosphorylation of Hic- 5 at tyrosine 60 by CAKbeta and Fyn. FEBS Lett 474: 179–183. 24. Tumbarello DA, Turner CE (2007) Hic-5 contributes to epithelial-mesenchymal transformation through a RhoA/ROCK-dependent pathway. J Cell Physiol 211: 736–747. 25. Klampfer L (2008) The role of signal transducers and activators of transcription in colon cancer. Front Biosci 13: 2888–2899. 26. Quesnelle KM, Boehm AL, Grandis JR (2007) STAT-mediated EGFR signaling in cancer. J Cell Biochem 102: 311–319. 27. Bunting KD (2007) STAT5 signaling in normal and pathologic hematopoiesis. Front Biosci 12: 2807–2820. 28. Tse JC, Kalluri R (2007) Mechanisms of metastasis: epithelial-to-mesenchymal transition and contribution of tumor microenvironment. J Cell Biochem 101: 816–829. 29. Vleminckx K, Vakaet L, Jr., Mareel M, Fiers W, van Roy F (1991) Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66: 107–119. 30. Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, et al. (1991) E-cadherin- mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 113: 173–185. 31. Birchmeier W, Behrens J (1994) Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta 1198: 11–26. 32. Agiostratidou G, Hulit J, Phillips GR, Hazan RB (2007) Differential cadherin expression: potential markers for epithelial to mesenchymal transformation during tumor progression. J Mammary Gland Biol Neoplasia 12: 127–133. 33. Li X, Martinez-Ferrer M, Botta V, Uwamariya C, Banerjee J, et al. (2011) Epithelial Hic-5/ARA55 expression contributes to prostate tumorigenesis and castrate responsiveness. Oncogene 30: 167–177. 34. Deakin NO, Turner CE (2010) Distinct roles for Paxillin and Hic-5 in regulating Breast Cancer cell morphology, invasion and metastasis. Mol Biol Cell. 35. Lee TK, Poon RT, Yuen AP, Ling MT, Kwok WK, et al. (2006) Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res 12: 5369–5376. 36. Hay ED (1995) An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) 154: 8–20. 37. Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, et al. (2007) Epithelial--mesenchymal and mesenchymal--epithelial transitions in carcinoma progression. J Cell Physiol 213: 374–383. PLoS ONE | www.plosone.org 7 April 2011 | Volume 6 | Issue 4 | e18878