Article

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

1. Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health
International journal of biological sciences (Impact Factor: 4.37). 01/2012; 8(8):1130-41. 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.

0 Bookmarks
 · 
60 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Accumulating evidences demonstrated that many long non-coding RNAs (lncRNAs) can cooperate with the adjacent coding genes, forming into "lncRNA-mRNA gene pairs" in multiple biological cellular processes. Here, we showed that a novel long non-coding RNA FOXCUT (FOXC1 promoter upstream transcript) and its neighboring gene FOXC1 played a similar important role in the oncogenesis and progression of esophageal squamous cell carcinoma (ESCC). In this study, the expression of FOXCUT/FOXC1 was measured in 82 ESCC tissues and adjacent noncancerous tissues by real-time quantitative PCR (qPCR). The prognostic significance of the lncRNA-mRNA gene pair was evaluated using Kaplan-Meier survival analysis and log-rank test. Cell biological experiments were performed in ESCC cell lines to explore their functions in tumor progression. Notably elevated FOXCUT and FOXC1 expression levels were observed in cancerous tissues compared to adjacent noncancerous tissues (86.6% and 84.1%, respectively; P < 0.01), showing strong correlations with poor differentiation, advanced lymph node classification and metastasis (P < 0.05). Moreover, patients with upregulated FOXCUT or FOXC1 experienced a significantly worse prognosis than those with downregulated FOXCUT or FOXC1 (P < 0.001 and P = 0.014, respectively). In addition, the expression of FOXCUT was positively correlated with expression of FOXC1 in ESCC specimens. And the expression of FOXC1 was also decreased as the FOXCUT expression was silenced by siRNA. Assays in vitro demonstrated that knockdown of either FOXCUT or FOXC1 remarkably inhibited cell proliferation, colony formation, migration, invasion in ESCC cells. In conclusion, FOXCUT may be functionally involved in the tumor progression and survival of ESCC patients, at least in part, by modulating FOXC1. FOXCUT and FOXC1 may function as a lncRNA-mRNA gene pair, which may represent a potential prognostic biomarker and therapeutic target for ESCC patients.
    International journal of clinical and experimental pathology. 01/2014; 7(6):2838-49.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background and purpose: Recently, evidence that Zinc transporter ZRT/IRT-like protein 4 (ZIP4) is involved in invasiveness and apoptosis has emerged in pancreatic cancer and prostate cancer. Our aim was to assess the role of ZIP4 in invasiveness, migration and apoptosis of hepatocellular carcinoma (HCC). The prognostic value of ZIP4 in HCC after liver transplantation was evaluated. Methods: The role of ZIP4 in HCC was investigated by overexpressing ZIP4 in BEL7402 and HepG2 cells and inhibiting ZIP4 in HuH-7 and HepG2 cells, using overexpression and shRNA plasmids in vitro studies. Immunohistochemical analysis was used to evaluate ZIP4 expression in HCC tissues from 60 patients undergoing liver transplantation, 36 cirrhotic tissue samples, and 6 normal tissue samples. Prognostic significance was assessed using the Kaplan-Meier method and the log-rank test. Results: Specific suppression of ZIP4 reduced cell migration and invasiveness, whereas ZIP4 overexpression caused increases in cell migration and invasiveness. Furthermore, overexpression of ZIP4 resulted in increased expression of pro-metastatic genes (MMP-2, MMP-9) and decreased expression of pro-apoptotic genes (caspase-3, caspase-9, Bax). In contrast, suppression of ZIP4 resulted in an opposite effect. ZIP4 was more highly expressed in tumor tissues than non-tumor tissues (P < 0.0001). ZIP4 expression was significantly associated with tumor recurrence (P = 0.002), tumor node metastasis stage (P = 0.044), Child-Turcotte-Pugh score (P = 0.042), and tumor size (P = 0.022). Univariate analysis showed that ZIP4 expression was significantly associated with overall survival (P = 0.020) and tumor-free survival (P = 0.049). Multivariate analysis revealed that ZIP4 was an independent predictor of overall survival (P = 0.037) after liver transplantation. Conclusions: ZIP4 could promote migration, invasiveness, and suppress apoptosis in hepatocellular carcinoma, and represent a novel predictor of poor prognosis and therapeutic target for patients with HCC who undergo liver transplantation.
    International journal of biological sciences 01/2014; 10(3):245-256. · 4.37 Impact Factor
  • Source
    [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".
    Molecular and Cellular Biochemistry 06/2014; · 2.39 Impact Factor

Preview

Download
0 Downloads
Available from