膜型基质金属蛋白酶-1在肝细胞癌侵袭和转移中作用机制的研究
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摘要
本研究通过免疫组织化学实验从蛋白水平观察MTl-MMP在大、小肝癌及癌旁组织和正常肝组织中的表达情况;通过克隆外源性人MT1-MMP基因及真核表达载体的构建和转染技术,从体内和体外两个方面观察人MT1-MMP对肝癌细胞生物行为学方面的影响,初步探讨MT1-MMP表达与肝癌侵袭转移的相关性,为肝癌的基因治疗奠定基础。
研究表明,MT1-MMP在肝癌组织中主要呈现胞膜、胞浆和胞核表达;并与肝癌的浸润、转移相关,MT1-MMP可能通过降解ECM或激活MMP-2参与肝癌的侵袭和转移,检测胞核MT1-MMP有助于预测肝癌的转移;MT1-MMP基因表达可在体内、体外促进肝癌细胞的黏附、迁移、浸润和转移能力,可能是通过活化MMP-2实现的,因而MT1-MMP有望成为抗肝癌侵袭的分子靶点。
随着MT1-MMP在肿瘤发生发展中作用研究的深入,MT1-MMP参与肿瘤的浸润和转移机制将逐渐阐明,这将为治疗肿瘤提供了新的靶点。
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world, which results in approximately one million people's death annually. The ratio of the incidence and the death rate of HCC is so high as 1: 0.98. The high death rate is mainly due to the strong capability of invasion and metastasis. The invasion and metastasis of HCC include multiple steps in which many factors are involved. Previous research showed that the invasiveness and metastasis ability of malignances was close related to the amount of the proteinase induced by the tumor cells, among which the matrix metalloproteinases (MMPs) were the most important elements. MT1-MMP was the first membrane-anchored MMP expressed in tumors to be identified as possessing the ability to activate proMMP-2.
To date, detailed function and expression patterns of MT1-MMP in HCC tissues and cells have not been reported. This study is designed to investigate the expression of MTl-MMP in HCC and to analyze its clinical significance. Furthermore, the study investigate the mechanism of MT1-MMP in tumor invasion and metastasis in vitro and in vivo.
The main methods of this study are as follows:
1.Immunohistochemical staining was performed to identify MT1-MMP protein location in HCC, para-cancerous and normal liver tissues. Furthermore, we studied the relationship between expression of MT1-MMP protein and clinic pathological feature in HCC.
2.Full-length human MT1-MMP cDNA was amplified from normal liver by RT-PCR and cloned into pMD18-T simple vector. After sequencing, the fragment was subcloned into the pcDNA3.1 vector and the recombinant eukaryotic expression vector was constructed. HepG2 cells stably transfected with the recombinant plasmids were selected by G418.
3.The expression levels of MT1-MMP mRNAs and proteins in HepG2 cells were detected by semi-quantitative reverse transcription- polymerase chain reaction (RT-PCR) and Western blot. Latent proMMP-2 and MMP-2 activity was analyzed by gelatin zymography. MTT was used to detect status of cell proliferation. Cell cycle after transfection was evaluated by flow cytometry. The adhesive, migratory and invasive abilities of HepG2 cells were measured via plate adhesion assay, cell scratch wound model and transwell chamber in vitro.
4.In the last part, the transfected HepG2 cell was injected into subcutis and spleen of nude mice. Tumor formation in the subcutis, spleen and liver were macroscopically counted 4 weeks after injection.
The main results of this study are as follows:
1.MT1-MMP protein is mainly expressed in membrane, cytoplasm and nucleus of HCC cells. However, it is mainly expressed in membrane in the liver tissues adjacent to cancer and normal liver tissues. Nucleus expression may be associated with poor prognosis in patients with liver cancer. MT1-MMP expression was significantly correlated with size, invasion and metastasis (P<0.05).
2.A 704 bp fragment was obtained by PCR, which is the same as the expectant fragment. Two fragments of PCR products (5400 bp and 704 bp) of eukaryotic expression vector pcDNA3.1/MT1-MMP were obtained by EcoR I and BamHI restriction enzyme digestion. Sequencing result was identical with that of reported MT1-MMP cDNA sequence in GenBank.
3.We obtained monocloned cell strains, which stably expressed MT1-MMP after selection by G418. MT1-MMP mRNA level of HepG2 cells that transfected with the recombinant vector was obviously higher (1.66±0.43) than that of empty vector group (1.21±0.25) and that of control group (1.19±0.18, P<0.01). MT1-MMP level of HepG2 cells that transfected with the recombinant vector was also higher than that of control group (P<0.01).
4.There were both 72, 000 precursor form and 64, 000 active form of MMP-2 in group that transfected with the recombinant vector, but there was only 72, 000 precursor form of MMP-2 in empty vector group and control group.
5.Compared with the controls,①there was a marked increase in cell proliferation (P<0.05).②a marked increase in cell viability, apoptosis significantly reduced (P<0.05).③the adhesive rate and migatory rate was up-regulated in MT1-MMP group (P<0.05).④expression of MT1-MMP gene significantly enhance the invasiveness of HepG2 cells in transwell insert invasion assay (P<0.05).
6.In the nude mice models, the inoculated tumor volumes of subcutis and spleen in the experimental group (511.0±121.1 mm3/346.1±60.3 mm3) were significantly different from those in the control group (327.8±54.0 mm3/213.81±32.9 mm3, P<0.05). The comparision of tumor weight between two groups is in accordance with that of tumor volume. The number of metastatic liver tumor in the experimental group was obviously more than that in control group (P<0.05).
The main conclusions of this study are as follows:
1.MT1-MMP can remarkably promote the invasive potential of HCC cells mainly through its ability of activating latent pro-MMP2 to degrade extracellular matrix.
2.MT1-MMP protein may promote the proliferation, invasion and metastasis of HepG2 cell both in vitro and in vivo.
研究表明,MT1-MMP在肝癌组织中主要呈现胞膜、胞浆和胞核表达;并与肝癌的浸润、转移相关,MT1-MMP可能通过降解ECM或激活MMP-2参与肝癌的侵袭和转移,检测胞核MT1-MMP有助于预测肝癌的转移;MT1-MMP基因表达可在体内、体外促进肝癌细胞的黏附、迁移、浸润和转移能力,可能是通过活化MMP-2实现的,因而MT1-MMP有望成为抗肝癌侵袭的分子靶点。
随着MT1-MMP在肿瘤发生发展中作用研究的深入,MT1-MMP参与肿瘤的浸润和转移机制将逐渐阐明,这将为治疗肿瘤提供了新的靶点。
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world, which results in approximately one million people's death annually. The ratio of the incidence and the death rate of HCC is so high as 1: 0.98. The high death rate is mainly due to the strong capability of invasion and metastasis. The invasion and metastasis of HCC include multiple steps in which many factors are involved. Previous research showed that the invasiveness and metastasis ability of malignances was close related to the amount of the proteinase induced by the tumor cells, among which the matrix metalloproteinases (MMPs) were the most important elements. MT1-MMP was the first membrane-anchored MMP expressed in tumors to be identified as possessing the ability to activate proMMP-2.
To date, detailed function and expression patterns of MT1-MMP in HCC tissues and cells have not been reported. This study is designed to investigate the expression of MTl-MMP in HCC and to analyze its clinical significance. Furthermore, the study investigate the mechanism of MT1-MMP in tumor invasion and metastasis in vitro and in vivo.
The main methods of this study are as follows:
1.Immunohistochemical staining was performed to identify MT1-MMP protein location in HCC, para-cancerous and normal liver tissues. Furthermore, we studied the relationship between expression of MT1-MMP protein and clinic pathological feature in HCC.
2.Full-length human MT1-MMP cDNA was amplified from normal liver by RT-PCR and cloned into pMD18-T simple vector. After sequencing, the fragment was subcloned into the pcDNA3.1 vector and the recombinant eukaryotic expression vector was constructed. HepG2 cells stably transfected with the recombinant plasmids were selected by G418.
3.The expression levels of MT1-MMP mRNAs and proteins in HepG2 cells were detected by semi-quantitative reverse transcription- polymerase chain reaction (RT-PCR) and Western blot. Latent proMMP-2 and MMP-2 activity was analyzed by gelatin zymography. MTT was used to detect status of cell proliferation. Cell cycle after transfection was evaluated by flow cytometry. The adhesive, migratory and invasive abilities of HepG2 cells were measured via plate adhesion assay, cell scratch wound model and transwell chamber in vitro.
4.In the last part, the transfected HepG2 cell was injected into subcutis and spleen of nude mice. Tumor formation in the subcutis, spleen and liver were macroscopically counted 4 weeks after injection.
The main results of this study are as follows:
1.MT1-MMP protein is mainly expressed in membrane, cytoplasm and nucleus of HCC cells. However, it is mainly expressed in membrane in the liver tissues adjacent to cancer and normal liver tissues. Nucleus expression may be associated with poor prognosis in patients with liver cancer. MT1-MMP expression was significantly correlated with size, invasion and metastasis (P<0.05).
2.A 704 bp fragment was obtained by PCR, which is the same as the expectant fragment. Two fragments of PCR products (5400 bp and 704 bp) of eukaryotic expression vector pcDNA3.1/MT1-MMP were obtained by EcoR I and BamHI restriction enzyme digestion. Sequencing result was identical with that of reported MT1-MMP cDNA sequence in GenBank.
3.We obtained monocloned cell strains, which stably expressed MT1-MMP after selection by G418. MT1-MMP mRNA level of HepG2 cells that transfected with the recombinant vector was obviously higher (1.66±0.43) than that of empty vector group (1.21±0.25) and that of control group (1.19±0.18, P<0.01). MT1-MMP level of HepG2 cells that transfected with the recombinant vector was also higher than that of control group (P<0.01).
4.There were both 72, 000 precursor form and 64, 000 active form of MMP-2 in group that transfected with the recombinant vector, but there was only 72, 000 precursor form of MMP-2 in empty vector group and control group.
5.Compared with the controls,①there was a marked increase in cell proliferation (P<0.05).②a marked increase in cell viability, apoptosis significantly reduced (P<0.05).③the adhesive rate and migatory rate was up-regulated in MT1-MMP group (P<0.05).④expression of MT1-MMP gene significantly enhance the invasiveness of HepG2 cells in transwell insert invasion assay (P<0.05).
6.In the nude mice models, the inoculated tumor volumes of subcutis and spleen in the experimental group (511.0±121.1 mm3/346.1±60.3 mm3) were significantly different from those in the control group (327.8±54.0 mm3/213.81±32.9 mm3, P<0.05). The comparision of tumor weight between two groups is in accordance with that of tumor volume. The number of metastatic liver tumor in the experimental group was obviously more than that in control group (P<0.05).
The main conclusions of this study are as follows:
1.MT1-MMP can remarkably promote the invasive potential of HCC cells mainly through its ability of activating latent pro-MMP2 to degrade extracellular matrix.
2.MT1-MMP protein may promote the proliferation, invasion and metastasis of HepG2 cell both in vitro and in vivo.
引文
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