Liver Cancer
Copyright ©2005 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 28, 2005; 11(40): 6269-6276
Published online Oct 28, 2005. doi: 10.3748/wjg.v11.i40.6269
Mechanism of metastasis by membrane type 1-matrix metalloproteinase in hepatocellular carcinoma
Ying-Chi Ip, Siu-Tim Cheung, Ka-Ling Leung, Sheung-Tat Fan
Ying-Chi Ip, Siu-Tim Cheung, Ka-Ling Leung, Sheung-Tat Fan, Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China
Author contributions: All authors contributed equally to the work.
Supported by the Seed Funding Program of the University of Hong Kong
Correspondence to: Dr. Siu -Tim Cheung, Department of Surgery, The University of Hong Kong, L9-55, Faculty of Medicine Building, 21 Sassoon Road, Hong Kong, China. stcheung@hkucc.hku.hk
Telephone: +852-28199651 Fax: +852-28184407
Received: March 17, 2005
Revised: April 6, 2005
Accepted: April 9, 2005
Published online: October 28, 2005
Abstract

AIM: To investigate the precise role of membrane type 1-matrix metalloproteinase (MT1-MMP) in hepatocellular carcinoma (HCC) metastasis.

METHODS: Human HCC cells Hep3B with overexpression of MT1-MMP were established by stable transfection, and compared with control cells carrying the empty vector. Cells were examined in vivo for their differences in the metastatic ability of athymic nude mice, and analyzed in vitro for their differences in invasion ability by invasion chamber coated with Matrigel, adhesion towards collagen I and migration through culture chamber. Cell proliferation and apoptosis in adherent and suspension status were evaluated by MTT and flow cytometry analysis.

RESULTS: We found that overexpression of MT1-MMP could increase intrahepatic metastasis in nude mice with orthotopic implantation of HCC cells (incidence of 100% [MT1-MMP transfectants] vs 40% [vector control transfectants], P<0.05). MT1-MMP could also enhance cell invasion through Matrigel (107.7 vs 39.3 cells/field, P<0.001), adhesion towards matrix (0.30 vs 0.12 absorbance unit at 540 nm, P<0.001), cell migration (89.3 vs 39.0 cells/field, P<0.001), and cell proliferation (24.3 vs 40.5 h/doubling, P<0.001). We also observed that MT1-MMP supported cell survival (71.4% vs 23.9%, P<0.001) with reduced apoptosis (43.7% vs 51.0%, P<0.05) in an attachment-free environment.

CONCLUSION: MT1-MMP overexpression could enhance metastasis. In addition to its active role in matrix degradation during tumor invasion, MT1-MMP enhances tumor cell survival upon challenge of detachment, which is important during metastasis when cells enter the circulation.

Keywords: MT1-MMP/MMP14; Liver cancer; Invasion; Metastasis