Expression of the serum response factor in hepatocellular carcinoma: Implications for epithelial-mesenchymal transition

Abstract

The acquisition of a migratory and invasive phenotype by cells of epithelial origin is associated with a gain of mesenchymal characteristics concomitant with a loss of the epithelial phenotype, a phenomenon referred to as epithelial-mesenchymal transition (EMT). Vimentin, a cytoplasmic intermediate filament, is characteristic of mesenchymal cells and is usually not expressed in epithelial cells. Increased expression of vimentin in carcinomas correlates with parameters of malignant potential such as tumor grade and tumor invasion. Serum response factor (SRF) regulates transcription of immediate early genes and triggers proliferation, migration and differentiation in several types of cells. However, the role of SRF in hepatocellular carcinoma (HCC) has not been explored. The aims of this study were to evaluate the expression of SRF and to assess a functional role of SRF in HCC. First, we examined the expression of SRF in 55 human specimens of HCC and four different HCC cell lines, including a sarcomatoid HCC cell line. We also examined the role of SRF in HCC by transfection of an SRF expression plasmid into a HCC cell line. SRF was expressed in 13 of 55 cases of HCC. SRF was predominantly expressed in HCC cells, with intense labeling in the nucleus. No staining was observed in hepatocytes of normal and cirrhotic liver outside the tumor. SRF was significantly up-regulated in high grade HCC, especially in sarcomatoid HCC. Overexpression of SRF in hepatocellular carcinoma cells accelerates migration and invasion with subsequent acquisition of mesenchymal phenotype by expression of a mesenchymal marker (vimentin) and activation of immediate early genes. We propose for the first time that the expression of SRF in HCC cells associated with EMT may play an important role in HCC progression. Thus, functional antagonism of SRF will provide an additional therapeutic approach by controlling tumor cell invasion and metastasis.

The Role of Novel 3d-Copper Cyanide Supramolecular Coordination Polymer in Epithelial Mesenchymal Transition Inhibition in Hepatocellular Carcinoma

“…The atypical expression of vimentin in epithelial cancer cells may be associated with local invasiveness and the potential for metastasis [41]. The aberrant overexpression of vimentin and its relation to tumor metastasis have been reported in HCC [42].…”

Role of serum response factor in the pathogenesis of disease

“…6 Several studies have shown a correlation between human cancer and elevated levels of SRF or SRF binding to CArG boxes. [99][100][101][102] Whether such increases in SRF are causative or merely reflective of human cancer is unclear. Recently, however, the liver-restricted miR-122 was shown to be attenuated in human hepatocellular carcinomas where SRF levels are elevated.…”

The expression and role of serum response factor in papillary carcinoma of the thyroid

“…For immunohistochemical staining of tissue samples, the Dako Envision system, that uses dextran polymers conjugated with horseradish peroxidase (Dako, Carpinteria, CA, USA) was performed, as described previously (12). The sections were incubated for 2 h at room temperature with anti-SRF (1:100 dilution; Santa Cruz Biotechnology, Santa Cruz, CA, USA).…”

“…Thyroid papillary carcinoma tissues were homogenized using an Ultra-Turrax homogenizer (Ika, Staufen, Germany) in ice-cold lysis buffer (50 mM Tris, pH 7.5, 150 mM NaCl, 0.5% Nonidet P-40) containing 1 mM phenylmethylsulfonyl fluoride, 2 μg/ml leupeptin, 2 μg/ml aprotinin, 5 mM sodium fluoride and 1 mM sodium orthovanadate. The lysates were subjected to Western blotting, as described previously (12). Since SRF is known to regulate expression of genes such as c-Fos, the expression levels of c-Fos and SRF protein were evaluated in an SRFtransfected cell line and thyroid papillary carcinoma tissues.…”

“…A previous study has demonstrated that SRF plays a role in tumor progression, specifically in the mesenchymal transition of epithelial tumor cells (11). We have recently reported that expression of SRF correlates with tumor cell dedifferentiation and enhances cell motility and invasiveness in hepatocellular carcinoma (HCC) cells (12).…”