Skip to main content

Advertisement

SpringerLink
Log in

FAK is involved in invasion and metastasis of hepatocellular carcinoma

  • Research Paper
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

Studies have shown that focal adhesion kinase (FAK) is overexpressed in several human tumors and plays an important role in tumor progression. However, the role and underlying mechanisms of FAK in hepatocellular carcinoma (HCC) progression remains to be elucidated. In this study, we examined FAK and phosphorylated FAK Tyr397 expression in a large series of HCCs. We found that both FAK and phosphorylated FAK Tyr397 were overexpressed in HCC samples and HCC cell lines. Increased FAK and phosphorylated FAK Tyr397 expressions were correlated with tumor stage, vascular invasion and intrahepatic metastasis in HCC. Furthermore, HCC cell adhesion, migration and invasion were substantially impaired by siRNA-mediated knockdown of FAK expression, whereas cell growth, apoptosis and cell cycle distribution were not affected. In addition, depletion of FAK induced a significant reduction in expressions and activities of both MMP-2 and MMP-9. Taken together, FAK contributes to invasion and metastasis of HCC partly through regulating expressions and activations of both MMP-2 and MMP-9, suggesting FAK could be a promising therapeutic target for HCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

ECM:

Extracellular matrix

FAK:

Focal adhesion kinase

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

HCC:

Hepatocellular carcinoma

MMP:

Matrix metalloproteinase

mRNA:

Messenger RNA

Phospho-FAK:

Phosphorylated FAK

RT-PCR:

Reverse transcription polymerase chain reaction

siRNA:

Small interfering RNA

Tyr:

Tyrosine

References

  1. Llovet JM, Burroughs A, Bruix J (2003) Hepatocellular carcinoma. Lancet 362(9399):1907–1917

    Article  PubMed  Google Scholar 

  2. McLean GW, Carragher NO, Avizienyte E, Evans J, Brunton VG, Frame MC (2005) The role of focal-adhesion kinase in cancer—a new therapeutic opportunity. Nat Rev Cancer 5(7):505–515

    Article  CAS  PubMed  Google Scholar 

  3. Siesser PM, Hanks SK (2006) The signaling and biological implications of FAK overexpression in cancer. Clin Cancer Res 12(11 Pt 1):3233–3237

    Article  CAS  PubMed  Google Scholar 

  4. Schlaepfer DD, Mitra SK, Ilic D (2004) Control of motile and invasive cell phenotypes by focal adhesion kinase. Biochim Biophys Acta 1692(2–3):77–102

    CAS  PubMed  Google Scholar 

  5. Chen HC, Appeddu PA, Isoda H, Guan JL (1996) Phosphorylation of tyrosine 397 in focal adhesion kinase is required for binding phosphatidylinositol 3-kinase. J Biol Chem 271(42):26329–26334

    Article  CAS  PubMed  Google Scholar 

  6. Chen HC, Guan JL (1994) Association of focal adhesion kinase with its potential substrate phosphatidylinositol 3-kinase. Proc Natl Acad Sci USA 91(21):10148–10152

    Article  CAS  PubMed  Google Scholar 

  7. Igishi T, Fukuhara S, Patel V, Katz BZ, Yamada KM, Gutkind JS (1999) Divergent signaling pathways link focal adhesion kinase to mitogen-activated protein kinase cascades. Evidence for a role of paxillin in c-Jun NH(2)-terminal kinase activation. J Biol Chem 274(43):30738–30746

    Article  CAS  PubMed  Google Scholar 

  8. Almeida EA, Ilić D, Han Q, Hauck CR, Jin F, Kawakatsu H et al (2000) Matrix survival signaling: from fibronectin via focal adhesion kinase to c-Jun NH(2)-terminal kinase. J Cell Biol 149(3):741–754

    Article  CAS  PubMed  Google Scholar 

  9. Kim SJ, Park JW, Yoon JS, Mok JO, Kim YJ, Park HK et al (2004) Increased expression of focal adhesion kinase in thyroid cancer: immunohistochemical study. J Korean Med Sci 19(5):710–715

    Article  CAS  PubMed  Google Scholar 

  10. Lark AL, Livasy CA, Dressler L, Moore DT, Millikan RC, Geradts J et al (2005) High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype. Mod Pathol 18(10):1289–1294

    Article  CAS  PubMed  Google Scholar 

  11. Miyazaki T, Kato H, Nakajima M, Sohda M, Fukai Y, Masuda N et al (2003) FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma. Br J Cancer 89(1):140–145

    Article  CAS  PubMed  Google Scholar 

  12. Lark AL, Livasy CA, Calvo B, Caskey L, Moore DT, Yang X et al (2003) Overexpression of focal adhesion kinase in primary colorectal carcinomas and colorectal liver metastases: immunohistochemistry and real-time PCR analyses. Clin Cancer Res 9(1):215–222

    CAS  PubMed  Google Scholar 

  13. Rovin JD, Frierson HF Jr, Ledinh W, Parsons JT, Adams RB (2002) Expression of focal adhesion kinase in normal and pathologic human prostate tissues. Prostate 53(2):124–132

    Article  CAS  PubMed  Google Scholar 

  14. Beierle EA, Massoll NA, Hartwich J, Kurenova EV, Golubovskaya VM, Cance WG et al (2008) Focal adhesion kinase expression in human neuroblastoma: immunohistochemical and real-time PCR analyses. Clin Cancer Res 14(11):3299–3305

    Article  CAS  PubMed  Google Scholar 

  15. Fujii T, Koshikawa K, Nomoto S, Okochi O, Kaneko T, Inoue S et al (2004) Focal adhesion kinase is overexpressed in hepatocellular carcinoma and can be served as an independent prognostic factor. J Hepatol 41(1):104–111

    Article  CAS  PubMed  Google Scholar 

  16. Itoh S, Maeda T, Shimada M, Aishima S, Shirabe K, Tanaka S et al (2004) Role of expression of focal adhesion kinase in progression of hepatocellular carcinoma. Clin Cancer Res 10(8):2812–2817

    Article  CAS  PubMed  Google Scholar 

  17. Chen JS, Wang Q, Fu XH, Huang XH, Chen XL, Cao LQ et al (2009) Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: association with MMP-9. Hepatol Res 39(2):177–186

    Article  CAS  PubMed  Google Scholar 

  18. Giannelli G, Bergamini C, Marinosci F, Fransvea E, Quaranta M, Lupo L et al (2002) Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma. Int J Cancer 97(4):425–431

    Article  CAS  PubMed  Google Scholar 

  19. Giannelli G, Fransvea E, Bergamini C, Marinosci F, Antonaci S (2003) Laminin-5 chains are expressed differentially in metastatic and nonmetastatic hepatocellular carcinoma. Clin Cancer Res 9(10 Pt 1):3684–3691

    CAS  PubMed  Google Scholar 

  20. Fransvea E, Angelotti U, Antonaci S, Giannelli G (2008) Blocking transforming growth factor-beta up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells. Hepatology 47(5):1557–1566

    Article  CAS  PubMed  Google Scholar 

  21. Ren K, Jin H, Bian C, He H, Liu X, Zhang S et al (2008) MR-1 modulates proliferation and migration of human hepatoma HepG2 cells through myosin light chains-2 (MLC2)/focal adhesion kinase (FAK)/Akt signaling pathway. J Biol Chem 283(51):35598–35605

    Article  CAS  PubMed  Google Scholar 

  22. Hauck CR, Hsia DA, Puente XS, Cheresh DA, Schlaepfer DD (2002) FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth. EMBO J 21(23):6289–62302

    Article  CAS  PubMed  Google Scholar 

  23. Bawadi HA, Bansode RR, Trappey A 2nd, Truax RE, Losso JN (2005) Inhibition of Caco-2 colon, MCF-7 and Hs578T breast, and DU 145 prostatic cancer cell proliferation by water-soluble black bean condensed tannins. Cancer Lett 218(2):153–162

    Article  CAS  PubMed  Google Scholar 

  24. Schlaepfer DD, Hauck CR, Sieg DJ (1999) Signaling through focal adhesion kinase. Prog Biophys Mol Biol 71(3–4):435–478

    Article  CAS  PubMed  Google Scholar 

  25. Schaller MD (2001) Biochemical signals and biological responses elicited by the focal adhesion kinase. Biochim Biophys Acta 1540(1):1–21

    Article  CAS  PubMed  Google Scholar 

  26. Liotta LA (1986) Tumor invasion and metastases—role of the extracellular matrix: Rhoads Memorial Award lecture. Cancer Res 46(1):1–7

    CAS  PubMed  Google Scholar 

  27. Curran S, Murray GI (1999) Matrix metalloproteinases in tumour invasion and metastasis. J Pathol 189(3):300–308

    Article  CAS  PubMed  Google Scholar 

  28. Vihinen P, Kähäri VM (2002) Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets. Int J Cancer 99(2):157–166

    Article  CAS  PubMed  Google Scholar 

  29. Vihinen P, Ala-aho R, Kähäri VM (2005) Matrix metalloproteinases as therapeutic targets in cancer. Curr Cancer Drug Targets 5(3):203–220

    Article  CAS  PubMed  Google Scholar 

  30. Parsons JT (2003) Focal adhesion kinase: the first ten years. J Cell Sci 116(Pt 8):1409–1416

    Article  CAS  PubMed  Google Scholar 

  31. Duxbury MS, Ito H, Benoit E, Zinner MJ, Ashley SW, Whang EE (2003) RNA interference targeting focal adhesion kinase enhances pancreatic adenocarcinoma gemcitabine chemosensitivity. Biochem Biophys Res Commun 311(3):786–792

    Article  CAS  PubMed  Google Scholar 

  32. Mitra SK, Lim ST, Chi A, Schlaepfer DD (2006) Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model. Oncogene 25(32):4429–4440

    Article  CAS  PubMed  Google Scholar 

  33. Canel M, Secades P, Garzón-Arango M, Allonca E, Suarez C, Serrels A et al (2008) Involvement of focal adhesion kinase in cellular invasion of head and neck squamous cell carcinomas via regulation of MMP-2 expression. Br J Cancer 98(7):1274–1284

    Article  CAS  PubMed  Google Scholar 

  34. Tsutsumi K, Kasaoka T, Park HM, Nishiyama H, Nakajima M, Honda T (2008) Tumor growth inhibition by synthetic and expressed siRNA targeting focal adhesion kinase. Int J Oncol 33(1):215–224

    CAS  PubMed  Google Scholar 

  35. Sonoda Y, Matsumoto Y, Funakoshi M, Yamamoto D, Hanks SK, Kasahara T (2000) Anti-apoptotic role of focal adhesion kinase (FAK). Induction of inhibitor-of-apoptosis proteins and apoptosis suppression by the overexpression of FAK in a human leukemic cell line, HL-60. J Biol Chem 275(21):16309–16315

    Article  CAS  PubMed  Google Scholar 

  36. Wu ZM, Yuan XH, Jiang PC, Li ZQ, Wu T (2006) Antisense oligonucleodes targeting the focal adhesion kinase inhibit proliferation, induce apoptosis and cooperate with cytotoxic drugs in human glioma cells. J Neurooncol 77(2):117–123

    Article  CAS  PubMed  Google Scholar 

  37. Jiang Y, Goldberg ID, Shi YE (2002) Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene 21(14):2245–2252

    Article  CAS  PubMed  Google Scholar 

  38. Sein TT, Thant AA, Hiraiwa Y, Amin AR, Sohara Y, Liu Y et al (2000) A role for FAK in the Concanavalin A-dependent secretion of matrix metalloproteinase-2 and -9. Oncogene 19(48):5539–5542

    Article  CAS  PubMed  Google Scholar 

  39. Hauck CR, Sieg DJ, Hsia DA, Loftus JC, Gaarde WA, Monia BP et al (2001) Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells. Cancer Res 61(19):7079–7090

    CAS  PubMed  Google Scholar 

  40. Mon NN, Ito S, Senga T, Hamaguchi M (2006) FAK signaling in neoplastic disorders: a linkage between inflammation and cancer. Ann N Y Acad Sci 1086:199–212

    Article  CAS  PubMed  Google Scholar 

  41. Halder J, Landen CN Jr, Lutgendorf SK, Li Y, Jennings NB, Fan D et al (2005) Focal adhesion kinase silencing augments docetaxel-mediated apoptosis in ovarian cancer cells. Clin Cancer Res 11:8829–8836

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (30672053) and the Science and Technology Planning Project of Guangdong Province, China (2008B030301036, 2009B030801014). We thank Key Laboratory of Tropical Disease Control Research of Ministry of Education, Sun Yat-Sen University for providing experimental instruments and equipment.

Author information

Authors and Affiliations

  1. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China

    Jing-Song Chen, Qian Wang, Xi-Lin Chen, Xin-Hui Fu & Hao-Xiang Tan

  2. Surgical Laboratory, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China

    Xiao-Hui Huang, Long-Juan Zhang, Wen Li & Jiong Bi

Authors
  1. Jing-Song Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-Hui Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xi-Lin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xin-Hui Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hao-Xiang Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Long-Juan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jiong Bi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qian Wang.

Additional information

J.-S. Chen and X.-H. Huang contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, JS., Huang, XH., Wang, Q. et al. FAK is involved in invasion and metastasis of hepatocellular carcinoma. Clin Exp Metastasis 27, 71–82 (2010). https://doi.org/10.1007/s10585-010-9306-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-010-9306-3

Keywords

Search

Navigation