MCT1、CD147在人肝癌中的表达及其反义RNA表达载体对肝癌细胞的影响
摘要
目的：在体外试验中使用CD147及MCT1反义RNA表达载体影响肝癌细胞表面MCT1的表达,观察它对肿瘤细胞内环境的干扰、对糖酵解代谢影响和抑制肿瘤细胞生长的作用。通过免疫组化方法检测人肝癌中MCT1和CD147的表达,探讨其表达与肿瘤临床及病理学的关系。
方法：体外实验采用HEPG2人肝癌细胞株进行实验。同时构建MCT1及CD147的反义RNA表达载体,用于转染HEPG2细胞株,HEPG2细胞分为未转染组,转染空质粒组和转染组,用western-blot方法检测MCT1及CD147质粒转染后对MCT1蛋白表达的影响,并用检测各组细胞内pHi及乳酸含量,绘制三组细胞的生长曲线并记录各组生长数据,以上资料均作统计学分析。收集湘雅医院2002年-2008年间60例肝癌手术切除标本,对照组50例为正常肝组织。将肝癌标本和对照正常肝组织标本制成石蜡切片并进行免疫组化染色,检测不同病理级别及临床分级肝癌组织标本和对照标本MCT1和CD147的表达水平。
结果：在细胞水平研究中,MCT1反义表达载体可抑制MCT1在细胞膜的表达,而CD147反义表达载体则可抑制MCT1在肿瘤细胞的功能,两种载体转染肝癌细胞后,均可引起肿瘤细胞pHi下降,细胞内乳酸堆积,细胞的生长受到抑制。肝癌标本中均有MCT1和CD147高表达,且临床病理级别高的肝癌组中二者表达水平低于于临床病理级别低的肝癌组,差异有统计学意义。
结论：运用MCT1及CD147反义RNA表达载体转染肝癌细胞,可影响MCT1的正常表达或功能,使得肿瘤细胞pHi降低、细胞内乳酸堆积、生长受到抑制。肝癌中存在MCT1和CD147的高表达,且MCT1及CD147表达水平与病理分级程度密切相关。MCT1及CD147与肝癌患者临床预后相关,两者表达水平高,更易复发,且生存期较短。
Objective:The study was to explore the expression level of MCT1 and CD 147 in human hepatocellular carcinoma,espacially the changes of expression level in different clinical phases and pathological grades by using immunohistochemical localization.MCTl and CD 147 gene anti-sense reconstructed vector were used to influence the experession of MCT1 on HEPG2,so that the lactic acid metabolism will be disturbed and cell growth will be delayed.
Methods:60 sections were obtained from patients with hepatocellular carcinoma. 50 cases with normal liver tissues were included into the control group.All sections were immunohistochemcally stained to observe the difference of CD147,MCT1 expression level between different pathological grade.Two kinds of anti-sense reconstructed vector (CD147 and MCT1)were transfected into the HEPG2.The cells were divided into three groups:HEPG2、HEPG2-PCIneo and HEPG2-PCI-MCT1(CD147).After transfection, the western-blot was used to detected the change of MCT1 expression. The pHi, intracellular lactic acid content and the tumor proliferation were recorded for comparison.
Results:The expression rates of CD147 and MCT1 in hepatocellular carcinoma tissues were 76.67% and 81.67%, respectively, which were significantly higher than those in normal liver tissue (P< 0.01). The expressions of CD147 and MCT1 were closely correlated with degree of differentiation and metastasis, but no association was observed with Child grades. There was a significant correlation between the expressions of CD147 and MCT1 in hepatocellular carcinoma (P< 0.01).
In cell culture trial,the expression of MCT1 were significantly changed after transfection of MCT1 gene anti-sense reconstructed vector.And after the transfection of CD147 gene anti-sense reconstructed vector,the MCT1 expression was invalid. After transfection, the pHi of HEPG2 was decreased.The lactic acid content increased,grow belocity retarted,doubling time increased(P<0.05).
Conclusion:The overexpressions of CD147 and MCT1 may be used as one of the objective marks to estimate the behaviors of hepatocellular carcinoma.The CD147,MCT1 anti-sense reconstructed vector could downregulated the expresion of the MCT1.And the hepatocellular carcinoma cell's lactic acid metabolim could be disturbed and cell growth could be delayed. We have found a new possible path for hepatocellular carcinoma therapy,but the detailed mechanism between MCT1 and CD 147 is remain uncertain and in vivo trial is necessary to research.
方法：体外实验采用HEPG2人肝癌细胞株进行实验。同时构建MCT1及CD147的反义RNA表达载体,用于转染HEPG2细胞株,HEPG2细胞分为未转染组,转染空质粒组和转染组,用western-blot方法检测MCT1及CD147质粒转染后对MCT1蛋白表达的影响,并用检测各组细胞内pHi及乳酸含量,绘制三组细胞的生长曲线并记录各组生长数据,以上资料均作统计学分析。收集湘雅医院2002年-2008年间60例肝癌手术切除标本,对照组50例为正常肝组织。将肝癌标本和对照正常肝组织标本制成石蜡切片并进行免疫组化染色,检测不同病理级别及临床分级肝癌组织标本和对照标本MCT1和CD147的表达水平。
结果：在细胞水平研究中,MCT1反义表达载体可抑制MCT1在细胞膜的表达,而CD147反义表达载体则可抑制MCT1在肿瘤细胞的功能,两种载体转染肝癌细胞后,均可引起肿瘤细胞pHi下降,细胞内乳酸堆积,细胞的生长受到抑制。肝癌标本中均有MCT1和CD147高表达,且临床病理级别高的肝癌组中二者表达水平低于于临床病理级别低的肝癌组,差异有统计学意义。
结论：运用MCT1及CD147反义RNA表达载体转染肝癌细胞,可影响MCT1的正常表达或功能,使得肿瘤细胞pHi降低、细胞内乳酸堆积、生长受到抑制。肝癌中存在MCT1和CD147的高表达,且MCT1及CD147表达水平与病理分级程度密切相关。MCT1及CD147与肝癌患者临床预后相关,两者表达水平高,更易复发,且生存期较短。
Objective:The study was to explore the expression level of MCT1 and CD 147 in human hepatocellular carcinoma,espacially the changes of expression level in different clinical phases and pathological grades by using immunohistochemical localization.MCTl and CD 147 gene anti-sense reconstructed vector were used to influence the experession of MCT1 on HEPG2,so that the lactic acid metabolism will be disturbed and cell growth will be delayed.
Methods:60 sections were obtained from patients with hepatocellular carcinoma. 50 cases with normal liver tissues were included into the control group.All sections were immunohistochemcally stained to observe the difference of CD147,MCT1 expression level between different pathological grade.Two kinds of anti-sense reconstructed vector (CD147 and MCT1)were transfected into the HEPG2.The cells were divided into three groups:HEPG2、HEPG2-PCIneo and HEPG2-PCI-MCT1(CD147).After transfection, the western-blot was used to detected the change of MCT1 expression. The pHi, intracellular lactic acid content and the tumor proliferation were recorded for comparison.
Results:The expression rates of CD147 and MCT1 in hepatocellular carcinoma tissues were 76.67% and 81.67%, respectively, which were significantly higher than those in normal liver tissue (P< 0.01). The expressions of CD147 and MCT1 were closely correlated with degree of differentiation and metastasis, but no association was observed with Child grades. There was a significant correlation between the expressions of CD147 and MCT1 in hepatocellular carcinoma (P< 0.01).
In cell culture trial,the expression of MCT1 were significantly changed after transfection of MCT1 gene anti-sense reconstructed vector.And after the transfection of CD147 gene anti-sense reconstructed vector,the MCT1 expression was invalid. After transfection, the pHi of HEPG2 was decreased.The lactic acid content increased,grow belocity retarted,doubling time increased(P<0.05).
Conclusion:The overexpressions of CD147 and MCT1 may be used as one of the objective marks to estimate the behaviors of hepatocellular carcinoma.The CD147,MCT1 anti-sense reconstructed vector could downregulated the expresion of the MCT1.And the hepatocellular carcinoma cell's lactic acid metabolim could be disturbed and cell growth could be delayed. We have found a new possible path for hepatocellular carcinoma therapy,but the detailed mechanism between MCT1 and CD 147 is remain uncertain and in vivo trial is necessary to research.
引文
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[1]Roy CC et al. Short-chain fatty acids:ready for prime time[J]? Nutr Clin Pract,2006,21 (4):351-366.
[2]曾军英,韩雪峰,谭支良.单羧酸转运蛋白家族及其生物学功能[J].生命的化学,2008,28(4)：404-407.
[3]Halestrap AP et al. The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond [J]. Pflugers Arch,2004,447 (5):619-628
[4]Halestrap AP et al. The proton-linked monocarboxylate transporter (MCT) family:structure, function and regulation[J]. Biochem J,1999,343 Pt 2:281-299
[5]Enerson BE et al. Molecular features, regulation, and function of monocarboxylate transporters:implications for drug delivery[J]. J Pharm Sci,2003,92(8):1531-1544
[6]Visser WE et al. Thyroid hormone transport by monocarboxylate transporters [J].Best Pract Res Clin Endocrinol Metab,2007,21(2): 223-236
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