Page 54 - Read Online

invasive Alexander cells, which remain unaffected. The fact that Fascin-1 silencing leads to migfilin and VASP
downregulation and increased adhesion indicates that
DISCUSSION Fascin-1 may regulate migfilin and VASP and/or be physically
associated with them. This evidence further complements
Cell adhesion proteins connecting cells to the ECM and/ recent work from our laboratory showing that migfilin
or to the neighboring cells are often interconnected to the silencing, among other things, reduces VASP expression,
actin-cytoskeleton and this network of interacting proteins is and leads to Fascin-1 upregulation, and promotion of cell
fundamental for tissue homeostasis while at the same time adhesion in HepG2 cells. Therefore, the evidence clearly
[12]
being deregulated in cancer and cancer metastasis. Fascin-1 indicates a molecular interplay between the three proteins,
[7,8]
is an actin-bundling protein that is found in membrane migfilin, Fascin-1, and VASP, and the potential existence of a
ruffles and stress fibers. The expression of Fascin-1 is regulatory feedback loop in HCC cells.
[19]
greatly increased in many transformed cells, as well as in
specialized normal cells including neuronal cells and antigen- Although our study was performed in cancer cell lines, which
presenting dendritic cells. A morphological characteristic have their limitations in terms of modeling the physiological
common to these cells expressing high levels of Fascin-1 is complexity of human cancer, it still offers significant insight
the development of many membrane protrusions in which into the molecular mechanism by which Fascin-1 is implicated
Fascin-1 is predominantly present. Recent studies show that in HCC pathogenesis. Of course, more studies are needed to
[9]
Fascin-1 also localizes to invadopodia, membrane protrusions decipher the exact sequence of molecular events taking place
formed at the adherent cell surface that facilitate ECM and the importance for HCC progression.
invasion, thus providing a potential molecular mechanism for
how Fascin-1 increases the invasiveness of cancer cells since Acknowledgments
Fascin-1 expression is upregulated in a spectrum of cancers We are grateful to Dr. Chuanyue Wu, Professor at the
such as breast cancer, colon cancer, pancreatic cancer, and University of Pittsburgh Medical School, Pittsburgh, PA, USA
prostate cancer. [20,21] In HCC, in particular, Fascin-1 has been for providing us with the anti-migfilin monoclonal antibody.
correlated with poor prognosis. [10]
Financial support and sponsorship
In fact, Fascin-1 has been recently introduced as a migration This study was supported by the European Association for the
factor associated with epithelial to mesenchymal transition in Study of the Liver Sheila Sherlock fellowship 2012.
HCC cells facilitating their invasiveness in combination with
[22]
matrix metalloproteinases. Moreover, it has been suggested Conflicts of interest
to be a novel marker of progression in HCC and a significant There are no conflicts of interest.
[11]
indicator of poor prognosis for HCC patients. However, little
is known regarding the molecular mechanism of its action. REFERENCES

In this study, we tested the expression and molecular 1. Runge D, Runge DM, Bowen WC, Locker J, Michalopoulos GK. Matrix
mechanism of action of Fascin-1 in two HCC cell lines that induced re-differentiation of cultured rat hepatocytes and changes of
differ in terms of aggressiveness; the hepatoma cell line CCAAT/enhancer binding proteins. Biol Chem 1997;378:873-81.
PLC/PRF/5 (Alexander) and the highly invasive HCC cell line 2. Gkretsi V, Mars WM, Bowen WC, Barua L, Yang Y, Guo L, St-Arnaud R,
HepG2. Interestingly, we show that Fascin-1 is dramatically Dedhar S, Wu C, Michalopoulos GK. Loss of integrin linked kinase from
upregulated in HepG2 cells compared to more benign mouse hepatocytes in vitro and in vivo results in apoptosis and hepatitis.
Hepatology 2007;45:1025-34.
Alexander cells [Figure 1a]. 3. Apte U, Gkretsi V, Bowen WC, Mars WM, Luo JH, Donthamsetty S, Orr
A, Monga SP, Wu C, Michalopoulos GK. Enhanced liver regeneration
We then utilized a siRNA-mediated silencing approach to following changes induced by hepatocyte-specific genetic ablation of
knock-down the Fascin-1 gene. Fascin-1 silencing led to a integrin-linked kinase. Hepatology 2009;50:844-51.
reduction in the expression level of two important focal 4. Gkretsi V, Apte U, Mars WM, Bowen WC, Luo JH, Yang Y, Yu YP, Orr A,
adhesion proteins related to the cytoskeleton, namely, St-Arnaud R, Dedhar S, Kaestner KH, Wu C, Michalopoulos GK. Liver-
migfilin [14,15] [Figure 1b], and its interactor VASP [Figure 2a]. [13] specific ablation of integrin-linked kinase in mice results in abnormal
histology, enhanced cell proliferation, and hepatomegaly. Hepatology
2008;48:1932-41.
More importantly, Fascin-1 silencing led to significantly 5. Gkretsi V, Bowen WC, Yang Y, Wu C, Michalopoulos GK. Integrin-
increased cell adhesion in the highly invasive and aggressive linked kinase is involved in matrix-induced hepatocyte differentiation.
HepG2 cells [Figure 2b] but had no effect on the less invasive Biochem Biophys Res Commun 2007;353:638-43.
Alexander cells, indicating that Fascin-1 silencing has, indeed, 6. Kensler TW, Qian GS, Chen JG, Groopman JD. Translational strategies
a great impact on more aggressive cells. Furthermore, the fact for cancer prevention in liver. Nat Rev Cancer 2003;3:321-9.
that it results in elevated cell adhesion in HepG2 cells shows 7. Jiang WG, Sanders AJ, Katoh M, Ungefroren H, Gieseler F, Prince M,
that Fascin-1 depletion stabilizes cell-ECM adhesions leading Thompson SK, Zollo M, Spano D, Dhawan P, Sliva D, Subbarayan PR,
Sarkar M, Honoki K, Fujii H, Georgakilas AG, Amedei A, Niccolai E,
to a less aggressive cancer phenotype. These findings are Amin A, Ashraf SS, Ye L, Helferich WG, Yang X, Boosani CS, Guha
evidence confirming previous studies showing the potential G, Ciriolo MR, Aquilano K, Chen S, Azmi AS, Keith WN, Bilsland
of Fascin-1 as a therapeutic target for metastasis. A, Bhakta D, Halicka D, Nowsheen S, Pantano F, Santini D. Tissue
[9]

Hepatoma Research | Volume 2 | Issue 2 | February 29, 2016 45