Expression of the serum response factor in hepatocellular carcinoma: implications for epithelial-mesenchymal transition.
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.
Park
Min Young
MY
Department of Pathology, Medical School and Institute for Medical Sciences, Chonbuk National University, Jeonju, Jeonbuk, Korea.
Kim
Kyung Ryoul
KR
Park
Ho Sung
HS
Park
Byung-Hyun
BH
Choi
Ha Na
HN
Jang
Kyu Yun
KY
Chung
Myoung Ja
MJ
Kang
Myoung Jae
MJ
Lee
Dong Geun
DG
Moon
Woo Sung
WS
D000293:Adolescent; D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000737:chemistry* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004848:Epithelium / Q000473:pathology*; D005260:Female; D017781:Genes, Immediate-Early; D006801:Humans; D008113:Liver Neoplasms / Q000737:chemistry* / Q000473:pathology; D008297:Male; D008648:Mesoderm / Q000473:pathology*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D012189:Retrospective Studies; D026362:Serum Response Factor / Q000032:analysis*; D014746:Vimentin / Q000032:analysis
D026362:Serum Response Factor; D014746:Vimentin