FOXC1 Contributes To Microvascular Invasion In Primary Hepatocellular Carcinoma Via Regulating Epithelial-Mesenchymal Transition

ArticleinInternational journal of biological sciences 8(8):1130-41 · September 2012with17 Reads
DOI: 10.7150/ijbs.4769 · Source: PubMed
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.
    • "EMT has been demonstrated to promote angiogenesis by modulating factors such as VEGF-A [7]. Because FOXC1 is an EMT-related gene, and the relationship between FOXC1 and VEGF-A has also been proved in hepatocellular cancer [7], here, we also revealed that the knockdown of FOXC1/ FOXCUT gene pair could lead to VEGF-A down-regulation. This may suggest a possible role for the FOXC1/FOXCUT gene pair in tumor angiogenesis in OSCC. "
    [Show abstract] [Hide abstract] ABSTRACT: The Fork head box C1 (FOXC1) gene is overexpressed in multiple malignant tumors and is functionally correlated with tumor progression. However, its' role in oral squamous cell carcinoma (OSCC) is still unclear. Recent studies have revealed that many long non-coding RNA (lncRNAs) cooperate with adjacent coding genes and form a functional "lncRNA-mRNA pair". In this study, we report a new lncRNA FOXC1 upstream transcript (FOXCUT) that was remarkably overexpressed in 23 OSCC patients, as was the adjacent FOXC1 gene. The expressions of FOXC1 and FOXCUT were positively correlated. When the expression of FOXCUT was down-regulated by small interfering RNA (siRNA), the expression of FOXC1 was also decreased. Moreover, in OSCC cells Tca8113 and SCC-9, down-regulation of either FOXC1 or FOXCUT by siRNA could inhibit cell proliferation and cell migration in vitro and was accompanied with a reduction of MMP2, MMP7, MMP9, and VEGF-A. In conclusion, FOXC1 may be co-amplified with FOXCUT in OSCC, and both of them may be functionally involved in the tumor progression of OSCC. This provides evidence that both FOXC1 and FOXCUT may serve as novel biomarkers and therapeutic targets in OSCC patients who overexpress this "lncRNA-mRNA pair".
    Article · Jun 2014
    • "Cell-invasion assay was performed using a transwell assay (Millipore, Billerica, MA). The details of this method had been described 16. The number of cells placed in the upper chamber was 3×104. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Over-expression of long non-coding RNA HOTAIR has been reported in several types of cancer. Yet its involvement in gastric cancer (GC) has not been well understood. The aim of present study was to examine the expression pattern of HOTAIR in GC patients, then, explore its role in promoting cancer invasion and underlying molecular mechanism. Methods: The expression level of HOTAIR in the tumor specimens of GC patients was quantified by Realtime RT-PCR. The correlation between HOTAIR level and clinicopathological factors as well as prognosis was then examined. Down-regulation of HOTAIR by RNA interference was applied to investigate its roles in tumor invasiveness via the view of Epithelial-to-mesenchymal transition (EMT). Results: The expression level of HOTAIR in cancer tissues was higher than that in adjacent noncancerous tissues. Expression level of HOTAIR was significantly correlated with lymph node metastasis and TNM stage. Furthermore, high expression level of HOTAIR was a predictor of poor over-all survival in GC patients. In vitro, inhibition of HOTAIR in GC cells could reduce invasiveness, as well as the expression of MMP1 and MMP3. In addition, suppression of HOTAIR could reverse EMT process. Conclusions: HOTAIR could act as a potential predictor for over-all survival in patients with GC. Inhibition of HOTAIR could reduce invasiveness and reverse EMT process in GC cells, indicating the potential role of HOTAIR in GC diagnostics and therapeutics.
    Full-text · Article · Jun 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Objective: To investigate if in vitro chemotherapy can induce the EMT progress in gastric cancer (GC) cells. Method: The GC cell line, SGC7901, was treated using 5-Fu at a concentration of 30 μg/mL. The residual cells after four cycles of 5-Fu therapy were named as SGC7901/Fu. The morphological changes and malignant biological features, including the invasiveness and clone formation ability and the characteristics of cancer stem cell and biomarkers of EMT between SGC7901 and SGC7901/Fu, were compared. Results: The SGC7901/Fu cells displayed a mesenchymal appearance, decreased the expression of epithelial markers, and increased the expression of mesenchymal markers. The 50% inhibitory concentrations in the SGC7901/Fu and SGC7901 cells were (43.8±7.2) and (64.6±5.5) μg/mL, respectively. The number of cells that migrated through the basement-membrane of the Transwell chamber was 51.4±8.7 and 93.2±9.5, respectively. The rate of clone formation was 5.2%±1.0% and 13.2%±2.2%, respectively. The portions of the CD44 +/CD24- cells were 4.13%±0.81% and 7.97%±0.50%, respectively. All differences were statistically significant (P<0.05). Conclusion: The residual GC cells underwent EMT progress after 5-Fu treatment, with increased chemoresistance and ability of invasiveness and acquired the property of cancer stem cells.
    Article · Sep 2013 · International journal of biological sciences
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