ABSTRACT
PURPOSE: To explore the molecular mechanism of Vascular endothelial growth factor receptor-1 (VEGFR-1) in invasion and metastasis of hepatocellular carcinoma. METHODS: Reverse transcription polymerase chain reaction was performed to test expression of VEGFR-1 and its ligand VEGF-B19 in four hepatoma carcinoma cell. Fluorescent immunohistochemistry and western blotting were used to test the change of expression of E-cadherin or α-catenin. RESULTS: VEGF-B-treated cells exhibited a change in E-cadherin from an organized, membrane-bound structure to a disorganized state that was dispersed throughout the cytoplasm. The maximal changes in E-cadherin were observed 24 hr after treatment of cells with VEGF-B. α-catenin was observed to translocate to the nucleus from its usual membrane-bound location 24 hr after treatment with either VEGF-B. Expression of the epithelial adhesion molecules E-cadherin was observed to decrease 48 hours after VEGF-B treatment. The nuclear expression of α-catenin was observed to increase 24 hr after treatment with VEGF-B. CONCLUSIONS: VEGFR-1 on tumor cells may contribute to the aggressive behavior of hepatocellular carcinoma cells by inducing epithelial to mesenchymal transition (EMT). Targeting VEGFR-1 and downstream mediators of EMT may provide the foundation for the development of novel therapeutic approaches for this morbid and lethal disease.
Subject(s)
Carcinoma, Hepatocellular/pathology , Epithelial-Mesenchymal Transition/drug effects , Liver Neoplasms/pathology , Vascular Endothelial Growth Factor Receptor-1/physiology , Cadherins/metabolism , Cell Line, Tumor , Humans , Vascular Endothelial Growth Factor B/pharmacology , alpha Catenin/metabolismABSTRACT
KiSS-1 has been identified as a putative metastasis-suppressor gene in human melanomas and breast cancer cell lines. Although loss of KiSS-1 expression has been associated with progression and poor prognosis of various cancers, the exact role of KiSS-1 expression in HCC is not well-defined. Our study investigated KiSS-1 expression levels in HCC and its role in invasion and metastasis of human HCC. The expression levels of KiSS-1 and MMP-9 protein were determined by tissue microarray (TMA) serial sections, immunohistochemistry and semi-quantitative image analysis. All clinical and histological data obtained were subjected to statistical analysis. The expression of KiSS-1 protein in HCC and intrahepatic metastasis lesions was significantly lower (P < 0.01) when compared with non-tumor liver tissue and normal liver tissue. Multivariate analysis revealed a significant inverse correlation between KiSS-1 expression and o1 TNM stage, (F = 7.113, P < 0.01) and o2 intrahepatic metastasis (t = 2.898, P < 0.01). Loss of KiSS-1 in intrahepatic metastasis versus primary carcinomas was statistically significant (P<0.01). We also found a negative correlation between KiSS-1 and MMP-9 expression in HCC (r = -0.506, P < 0.01). We conclude that loss of KiSS-1 during HCC metastasis, along with a concomitant upregulation of MMP-9 suggests a possible mechanism for cell motility and invasion during HCC metastasis, with KiSS-1 emerging as a possible therapeutic target during HCC metastasis.
