title: Serum response factor induces epithelial to mesenchymal transition with resistance to sorafenib in hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Department of Pathology, Chonbuk National University, Medical School, Research Institute of Clinical Medicine of Chonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 561-756, Republic of Korea.
authors.forename: Jun Sang
authors.initials: JS
authors.lastname: Bae
authors.forename: Sang Jae
authors.initials: SJ
authors.lastname: Noh
authors.forename: Kyoung Min
authors.initials: KM
authors.lastname: Kim
authors.forename: Kyu Yun
authors.initials: KY
authors.lastname: Jang
authors.forename: Myoung Ja
authors.initials: MJ
authors.lastname: Chung
authors.forename: Dae Gohn
authors.initials: DG
authors.lastname: Kim
authors.forename: Woo Sung
authors.initials: WS
authors.lastname: Moon
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*; D000077157:Sorafenib; D014746:Vimentin / Q000378:metabolism
chemical_list: D010671:Phenylurea Compounds; D026362:Serum Response Factor; D014746:Vimentin; D009536:Niacinamide; D000077157:Sorafenib