Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition.
OBJECTIVE
Hepatocellular carcinoma (HCC) is a rapidly growing tumor associated with a high propensity for vascular invasion and metastasis. Epithelial-mesenchymal transition (EMT) is a key event in the tumor invasion process. Recently, Twist has been identified to play an important role in EMT-mediated metastasis through the regulation of E-cadherin expression. However, the actual role of Twist in tumor invasiveness remains unclear. The purpose of this study is to investigate the expression and possible role of Twist in HCC.


METHODS
We evaluated Twist and E-cadherin expression in HCC tissue microarray of paired primary and metastatic HCC by immunohistochemical staining. The role of Twist in EMT-mediated invasiveness was also evaluated in vitro in HCC cell lines.


RESULTS
We first showed that overexpression of Twist was correlated with HCC metastasis (P=0.001) and its expression was negatively correlated with E-cadherin expression (P=0.001, r=-0.443) by tissue microarray. A significant increase of Twist at the mRNA level was also found in metastatic HCC cell lines MHCC-97H, MHCC-97L, and H2M when compared with nonmetastatic Huh-7, H2P, and PLC cell lines. The MHCC-97H cell line, which has a higher metastatic ability, was found to have a higher level of Twist than MHCC-97L. Accompanied with increased Twist expression in the metastatic HCC cell lines when compared with the nonmetastatic primary ones, we found decreased E-cadherin mRNA expression in the metastatic HCC cell lines. By ectopic transfection of Twist into PLC cells, Twist was able to suppress E-cadherin expression and induce EMT changes, which was correlated with increased HCC cell invasiveness.


CONCLUSIONS
This study shows that Twist overexpression was correlated with HCC metastasis through induction of EMT changes and HCC cell invasiveness.
Lee
Terence K
TK
Centre for the Study of Liver Disease, and Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China.
Poon
Ronnie T P
RT
Yuen
Anthony P
AP
Ling
Ming Tat
MT
Kwok
Wei Kei
WK
Wang
Xiang Hong
XH
Wong
Yong Chuan
YC
Guan
Xin Yuan
XY
Man
Kwan
K
Chau
King Lok
KL
Fan
Sheung Tat
ST
D015820:Cadherins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D046228:Microarray Analysis / Q000379:methods; D009361:Neoplasm Invasiveness / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism*; D013223:Statistics as Topic; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D015854:Up-Regulation
D015820:Cadherins; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1