Fascin-1 depletion from hepatocellular carcinoma cells inhibits migfilin and vasodilator-stimulated phosphoprotein expression and enhances adhesiona

Abstract

Aim: Extracellular matrix (ECM)-adhesions and their interaction with actin cytoskeleton are fundamental for hepatocellular carcinoma (HCC). Fascin-1, an actin-bundling protein, is correlated with poor HCC prognosis, and is known regarding the molecular mechanism of its action. In this study, the authors investigated Fascin-1 basic molecular mechanism and cellular properties in HCC cells.

Methods: Fascin-1 was silenced by small interfering RNA and the expression of actin. The ECM-adhesion-related proteins were assessed along with the cells’ adhesion capacity in two cell lines that differ in terms of aggressiveness; the hepatoma cell line PLC/PRF/5 (Alexander) and the highly invasive HCC cell line HepG2.

Results: This study shows that Fascin-1 is upregulated in HepG2 cells compared to Alexander cells and when silenced leads to increased cell adhesion only in HepG2, while at the same time is associated with reduced migfilin and vasodilator-stimulated phosphoprotein (VASP) expression.

Conclusion: This is the first study to show that Fascin-1 contributes to a more aggressive phenotype in HCC cells and acts through migfilin and VASP.

Keywords

Adhesion / Fascin-1 / hepatocellular carcinoma / migfilin / vasodilator-stimulated phosphoprotein

References

[1] Runge D,Bowen WC,Michalopoulos GK.Matrix induced re-differentiation of cultured rat hepatocytes and changes of CCAAT/enhancer binding proteins..Biol Chem1997;378:873-81

[2] Gkretsi V,Bowen WC,Yang Y,St-Arnaud R,Wu C.Loss of integrin linked kinase from mouse hepatocytes in vitro and in vivo results in apoptosis and hepatitis..Hepatology2007;45:1025-34

[3] Apte U,Bowen WC,Luo JH,Orr A,Wu C.Enhanced liver regeneration following changes induced by hepatocyte-specific genetic ablation of integrin-linked kinase..Hepatology2009;50:844-51 PMCID:PMC2914599

[4] Gkretsi V,Mars WM,Luo JH,Yu YP,St-Arnaud R,Kaestner KH,Michalopoulos GK.Liver-specific ablation of integrin-linked kinase in mice results in abnormal histology, enhanced cell proliferation, and hepatomegaly..Hepatology2008;48:1932-41 PMCID:PMC2597430

[5] Gkretsi V,Yang Y,Michalopoulos GK.Integrin-linked kinase is involved in matrix-induced hepatocyte differentiation..Biochem Biophys Res Commun2007;353:638-43 PMCID:PMC1769419

[6] Kensler TW,Chen JG.Translational strategies for cancer prevention in liver..Nat Rev Cancer2003;3:321-9

[7] Jiang WG,Katoh M,Gieseler F,Thompson SK,Spano D,Sliva D,Sarkar M,Fujii H,Amedei A,Amin A,Ye L,Yang X,Guha G,Aquilano K,Azmi AS,Bilsland A,Halicka D,Pantano F.Tissue invasion and metastasis: molecular, biological and clinical perspectives..Semin Cancer Biol2015;pii:S1044-579X(15)00023-1doi:10.1016/j.semcancer.2015.03.008.

[8] Canel M,Frame MC.E-cadherin-integrin crosstalk in cancer invasion and metastasis..J Cell Sci2013;126:393-401

[9] Chen L,Jakoncic J,Huang XY.Migrastatin analogues target fascin to block tumour metastasis..Nature2010;464:1062-6 PMCID:PMC2857318

[10] Huang X,Xue H,Han X,Zhang J.Fascin and cortactin expression is correlated with a poor prognosis in hepatocellular carcinoma..Eur J Gastroenterol Hepatol2012;24:633-9

[11] Iguchi T,Umeda K,Fujita N,Gion T,Maehara Y.Fascin expression in progression and prognosis of hepatocellular carcinoma..J Surg Oncol2009;100:575-9

[12] Gkretsi V.Experimental evidence of Migfilin as a new therapeutic target of hepatocellular carcinoma metastasis..Exp Cell Res2015;334:219-27

[13] Zhang Y,Gkretsi V.Migfilin interacts with vasodilator- stimulated phosphoprotein (VASP) and regulates VASP localization to cell-matrix adhesions and migration..J Biol Chem2006;281:12397-407

[14] Gkretsi V,Tu Y,Stolz DB,Watkins SC.Physical and functional association of migfilin with cell-cell adhesions..J Cell Sci2005;118:697-710

[15] Tu Y,Shi X,Wu C.Migfilin and Mig-2 link focal adhesions to filamin and the actin cytoskeleton and function in cell shape modulation..Cell2003;113:37-47

[16] Castellano F,Patin D,Chavrier P.A WASp- VASP complex regulates actin polymerization at the plasma membrane..EMBO J2001;20:5603-14 PMCID:PMC125672

[17] Sechi AS.ENA/VASP proteins: multifunctional regulators of actin cytoskeleton dynamics..Front Biosci2004;9:1294-310

[18] Kwiatkowski AV,Loureiro JJ.Function and regulation of Ena/VASP proteins..Trends Cell Biol2003;13:386-92

[19] Adams JC.Fascin protrusions in cell interactions..Trends Cardiovasc Med2004;14:221-6

[20] Tan VY,Adams JC.Association of Fascin-1 with mortality, disease progression and metastasis in carcinomas: a systematic review and meta-analysis..BMC Med2013;11:52 PMCID:PMC3635876

[21] Kulasingam V.Fascin-1 is a novel biomarker of aggressiveness in some carcinomas..BMC Med2013;11:53 PMCID:PMC3626678

[22] Hayashi Y,Lee GH.Fascin-1 expression correlates with repression of E-cadherin expression in hepatocellular carcinoma cells and augments their invasiveness in combination with matrix metalloproteinases..Cancer Sci2011;102:1228-35