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Clinical Cancer Research Vol. 12, 5369-5376, September 15, 2006
© 2006 American Association for Cancer Research


Human Cancer Biology

Twist Overexpression Correlates with Hepatocellular Carcinoma Metastasis through Induction of Epithelial-Mesenchymal Transition

Terence K. Lee1,2, Ronnie T.P. Poon1,2, Anthony P. Yuen2, Ming Tat Ling3, Wei Kei Kwok2, Xiang Hong Wang3, Yong Chuan Wong3, Xin Yuan Guan1,4, Kwan Man1,2, King Lok Chau1,2 and Sheung Tat Fan1,2

Authors' Affiliations: 1 Centre for the Study of Liver Disease, and Departments of 2 Surgery, 3 Anatomy, and 4 Clinical Oncology, The University of Hong Kong, Pokfulam, Hong Kong, China

Requests for reprints: Ronnie T.P. Poon, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong. Phone: 852-2855-3641; Fax: 852-2817-5475; E-mail: poontp{at}hkucc.hku.hk.

Purpose: 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.

Experimental Design: 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.

Conclusion: This study shows that Twist overexpression was correlated with HCC metastasis through induction of EMT changes and HCC cell invasiveness.




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Copyright © 2006 by the American Association for Cancer Research.