Mechanism of metastasis by membrane type 1-matrix metalloproteinase in hepatocellular carcinoma
Mechanism of metastasis by membrane type 1-matrix metalloproteinase in hepatocellular carcinoma
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DOI：
10.3748/wjg.v11.i40.6269
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发表时间：
2005-10-28
影响因子：
4.3
通讯作者：
Fan, Sheung-Tat
中科院分区：
文献类型：
--
作者：
Ip, Ying-Chi;Cheung, Siu-Tim;Fan, Sheung-Tat
目的：探讨膜型1-基质金属蛋白酶（MT1-MMP）在肝细胞癌（HCC）转移中的确切作用。方法：通过稳定转染建立MT1-MMP过表达的人肝癌细胞Hep3B，并与携带空载体的对照细胞进行比较。在体内检测细胞在胸腺裸鼠体内转移能力的差异，并在体外通过包覆Matrigel的侵袭室、对I型胶原的粘附以及通过培养室的迁移分析细胞在侵袭能力上的差异。用MTT和流式细胞术观察细胞在贴壁和悬浮状态下的增殖和凋亡情况。结果：我们发现MT1-MMP过表达可增加原位肝癌移植裸鼠肝内转移（MT1-MMP转染的发生率为100%，载体对照转染的发生率为40%，P < 0.05）。MT1-MMP还可以通过Matrigel增强细胞侵袭（107.7 vs 39.3个细胞/场，P < 0.001），对基质的粘附（540 nm吸光度单位0.30 vs 0.12, P < 0.001），细胞迁移（89.3 vs 39.0个细胞/场，P < 0.001）和细胞增殖（24.3 vs 40.5个小时/场，P < 0.001）。我们还观察到，在无附着环境中，MT1-MMP支持细胞存活（71.4%对23.9%,P < 0.001），减少凋亡（43.7%对51.0%,P < 0.05）。结论：MT1-MMP过表达可促进肿瘤转移。除了在肿瘤侵袭过程中对基质降解有积极作用外，MT1-MMP还能增强肿瘤细胞脱离挑战时的存活，这在细胞进入循环后的转移过程中很重要。(C) 2005 WJG出版社和爱思唯尔公司。版权所有。
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. (C) 2005 The WJG Press and Elsevier Inc. All rights reserved.