FOXC1 Contributes To Microvascular Invasion In Primary Hepatocellular Carcinoma Via Regulating Epithelial-Mesenchymal Transition
Open Access
- 1 January 2012
- journal article
- Published by Ivyspring International Publisher in International Journal of Biological Sciences
- Vol. 8 (8), 1130-1141
- https://doi.org/10.7150/ijbs.4769
Abstract
The existence of microvascular invasion (MVI) formation is one of the most important risk factors predicting poor outcome in hepatocellular carcinoma (HCC) and its mechanism remains largely unknown. Epithelial-Mesenchymal Transition (EMT) has been suggested to be involved in many steps of the invasion-metastasis cascade. To elucidate the possible contribution of EMT to MVI, we initially evaluated the expression of 8 EMT-related transcription factors (TFs) in HCC patients with or without MVI and found that FOXC1 expression was significantly higher in patients with MVI than those without MVI (P < 0.05). Knockdown of FOXC1 expression in HCC cells resulted in a partial conversion of their EMT progresses, mainly regulating the mesenchymal component. Ectopic expression of snail, twist or TGF-β1 could induce expression of FOXC1, but none of the expression of snail, twist, slug or TGF-β was consistently down-regulated in response to FOXC1 silencing, suggesting FOXC1 might operate the downstream of other EMT regulators. In addition, knockdown of FOXC1 expression led to cytoskeleton modification accompanied by decreased ability of cell proliferation, migration, and invasion. Meanwhile, some matrix metalloproteinases (MMPs) and VEGF-A were also simultaneously down-regulated. Together, our findings demonstrate that FOXC1 is one of candidate predictive markers of MVI, and that inhibition of FOXC1 expression can partially reverse EMT program, offering a potential molecular therapeutic target for reducing tumor metastasis in HCC patients.Keywords
This publication has 32 references indexed in Scilit:
- The Forkhead Box Transcription Factor FOXC1 Promotes Breast Cancer Invasion by Inducing Matrix Metalloprotease 7 (MMP7) ExpressionPublished by Elsevier BV ,2012
- Cortical dysplasia and skull defects in mice with a Foxc1 allele reveal the role of meningeal differentiation in regulating cortical developmentProceedings of the National Academy of Sciences of the United States of America, 2007
- Mesenchyme Forkhead 1 ( FOXC2 ) plays a key role in metastasis and is associated with aggressive basal-like breast cancersProceedings of the National Academy of Sciences of the United States of America, 2007
- Long-term Therapy With Adefovir Dipivoxil for HBeAg-Negative Chronic Hepatitis B for up to 5 YearsGastroenterology, 2006
- The Spemann organizer gene, Goosecoid , promotes tumor metastasisProceedings of the National Academy of Sciences of the United States of America, 2006
- Identification of Tgfbeta1i4 as a downstream target of Foxc1Development, Growth & Differentiation, 2006
- Transendothelial Migration of Melanoma Cells Involves N-Cadherin-mediated Adhesion and Activation of the β-Catenin Signaling PathwayMolecular Biology of the Cell, 2005
- DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cellsOncogene, 2005
- Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor MetastasisCell, 2004
- Long-Term Results With Multimodal Adjuvant Therapy and Liver Transplantation for the Treatment of Hepatocellular Carcinomas Larger Than 5 CentimetersAnnals of Surgery, 2002