Epithelial to mesenchymal transition is associated with shorter disease-free survival in hepatocellular carcinoma.
BACKGROUND
Epithelial to mesenchymal transition (EMT) is involved in cancer cell invasion and metastasis as well as chemoresistance. Elucidation of EMT in hepatocellular carcinoma (HCC) might contribute to deeper understanding of its biology.


METHODS
Overall, 100 patients with HCC, who underwent resection, were analyzed. The messenger RNA (mRNA) expression of the epithelial marker E-cadherin and the mesenchymal marker Vimentin were measured, and the EMT status of each patient was determined as follows: Vimentin/E-cadherin <2 = Epithelial (E), Vimentin/E-cadherin ≥2 = Mesenchymal (M). The correlation between these values and clinicopathological factors and prognosis were analyzed statistically. Moreover, the expression of transcription factors involved in EMT (Twist-1, Snail, Slug, Zeb-1, and Zeb-2) were measured and the role of interleukin (IL)-6 in inducing EMT and chemoresistance was examined.


RESULTS
Patients with a mesenchymal tumor were more prone to have an earlier recurrence than those with an epithelial tumor. EMT-inducing transcription factors were more highly expressed in mesenchymal tumors than in epithelial tumors, and Twist-1 and Zeb-2 were significantly overexpressed. α-Fetoprotein (AFP) values were significantly higher in patients with epithelial tumors, and AFP-expressing HCC cell lines were more responsive to sorafenib. IL-6 expression was significantly higher in mesenchymal tumors, and knockdown of IL-6 in mesenchymal HCC cell lines increased E-cadherin expression and sensitivity to sorafenib.


CONCLUSIONS
Analysis of surgically resected tumors suggests that EMT is involved in early disease recurrence in HCC. Twist-1 and Zeb-2 might be important for inducing EMT, and IL-6 might be a potential therapeutic target for alleviating the chemoresistance of mesenchymal HCC tumors.
Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan, suguru@med.nagoya-u.ac.jp.
Suguru
S
Yamada
Norio
N
Okumura
Lan
L
Wei
Bryan C
BC
Fuchs
Tsutomu
T
Fujii
Hiroyuki
H
Sugimoto
Shuji
S
Nomoto
Shin
S
Takeda
Kenneth K
KK
Tanabe
Yasuhiro
Y
Kodera
D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D008297:Male; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000235:genetics / Q000378:metabolism
D014408:Biomarkers, Tumor; C508600:IL6 protein, human; D015850:Interleukin-6; D009687:Nuclear Proteins; D012333:RNA, Messenger; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D000509:alpha-Fetoproteins