The epithelial to mesenchymal transition (EMT) is a crucial process in
tumor progression. EMT of
tumor cells not only causes increased
metastasis, but also contributes to drug resistance.
Serum response factor (SRF) is a
transcription factor that plays a central role in
carcinogenesis and
tumor progression in several types of
cancers. We investigated the effect of EMT-related SRF, focusing on its promotion of chemoresistance against
sorafenib in
hepatocellular carcinoma (HCC). We examined SRF and Snail expression in 146 cases of HCCs by immunohistochemistry. We also examined the chemoresistance effect of SRF in HCC cells by transfecting HLE cells with SRF
cDNA and SH-J1 cells with SRF antisense
cDNA. Expression of SRF and Snail were detected in 37.6% (55 of 146 cases) and in 12.3% (18 of 146 cases) of the HCCs, respectively. None of the
tumor-free liver tissues showed SRF or Snail expression. SRF expression was closely correlated with the expression of Snail (p<0.001) and expression of both SRF and Snail showed significant correlation with the high histological grade (p=0.015 and 0.003, respectively). Overexpression of SRF in HLE cells led to increased expression of mesenchymal markers, as well as increased cell growth and colony formation. Overexpression of SRF also led to a significant reduction in the cytotoxic effect of
sorafenib in HLE cells. Conversely, inhibition of SRF expression in the SH-J1 cells significantly enhanced the apoptotic effects of
sorafenib, along with the reduced expression of mesenchymal markers and restored the expression of
E-cadherin. These results suggest that SRF is critical for HCC to acquire a mesenchymal phenotype, which leads to resistance against a
sorafenib-mediated apoptotic effect.