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单酰甘油脂肪酶对人肝细胞癌裸鼠移植瘤的影响及其机制
Influence of monoacylglycerol lipase on growth of nude mice xenograft tumor of human hepatocellular carcinoma and related mechanism
文章发布日期:2019年06月14日  来源:  作者:余家建,张俊勇,范德庆  点击次数:209次  下载次数:51次

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【摘要】:目的探讨单酰甘油脂肪酶(MAGL)在人肝细胞癌(HCC)裸鼠移植瘤生长中的作用和机制。方法 移植的SMMC-7721细胞株分为SMMC-7721WT组(未处理)、SMMC-7721MAGL-KD组(MAGL沉默)、SMMC-7721MAGL-OE组(MAGL过表达)和SMMC-7721Vector组(空载体转染)4组。将27只雄性BALB/c裸鼠分为4组建立裸鼠皮下移植瘤模型,即A组(注射SMMC-7721WT组细胞株,n=12)、B组(注射SMMC-7721MAGL-KD组细胞株,n=5)、C组(注射SMMC-7721MAGL-OE组细胞株,n=5)及D组(注射SMMC-7721Vector组细胞株,n=5),其中A组又分为A1(正常饲喂,n=4)、A2[(高脂饲喂(HFD)+JZL184(MAGL的特异性抑制剂,n=4)和A3 (HFD饲喂,n=4)3个亚组。观察并比较4组肿瘤体积变化,瘤体内增殖细胞核抗原(PCNA)、金属基质蛋白酶(MMP)2、血浆溶血性磷脂酸(LPA)和前列腺素E2(PGE2)的表达水平。计量资料多组间比较采用单因素方差分析,进一步两两比较采用SNK-q检验。结果MMC-7721WT组、SMMC-7721MAGL-KD组、SMMC-7721MAGL-OE组3组间MAGL蛋白相对表达水平比较差异有统计学意义(0.377±0.026 vs 0.182±0.055 vs 0.689±0.019, F=33.382, P<0001),SMMC-7721MAGL-KD组MAGL蛋白表达水平显著低于SMMC-7721WT组(P<0.05),SMMC-7721MAGL-OE组显著高于SMMC-7721WT组(P<0.05);A、B、C、D 4组间裸鼠皮下移植瘤大小比较差异有统计学意义[(4236.125±1284.283) mm3 vs (1883.375±552.977) mm3 vs (10 146.061±1842.264) mm3 vs (4307.452±2070.708) mm3, F=6.804, P=0.023],C组的裸鼠皮下移植瘤的生长速度比A组更快(P<005),而B组比A组慢(P<0.05);A、B、C 3组间PCNA和MMP2水平比较差异均有统计学意义(PCNA:25 843.821±4201310 vs 17 426.95±5139.202 vs 39 753.103±5721.444, F=21.482, P<0.001; MMP2: 52 841.621±4339.253 vs 35 511.451±8251.423 vs 68 274.731±6418.594, F=11.526, P<0.001),B组PCNA和MMP2水平均明显低于A组( P值均<0.05),而C组均高于A组(P值均<0.05);A1、A2、A3 3组间肿瘤体积比较差异有统计学意义[(23 476.289±483.872) mm3 vs (18 593.851±1385.805) mm3 vs (37 703.198±2925.254) mm3, F=47.371, P=0.004],与A1组相比,A3组的裸鼠皮下移植瘤体积增长速度更快(P<005),A2组明显受到抑制(P<0.05);A1、A2、A3 3组间PGE2水平比较差异有统计学意义[(0.109±0.023) μmol/L vs (0.056±0.010) μmol/L vs (0.168±0.024) μmol/L, F=16.492, P<0.001],A3组PGE2水平明显高于A1组(P<0.05),A2组明显低于A1组(P<0.05);B、C、D 3组间PGE2水平比较差异有统计学意义[(0.069±0.025) μmol/L vs (0.175±0.023) μmol/L vs (0.096±0.019) μmol/L, F=31.550, P<0.001],B组PGE2水平明显低于D组(P<0.05),C组明显高于D组(P<005)。结论 MAGL可能通过调控PGE2促进裸鼠HCC皮下移植瘤的生长,提示MAGL可能成为未来治疗HCC的潜在靶点。
【Abstract】:ObjectiveTo investigate the role and mechanism of action of monoacylglycerol lipase (MAGL) on the growth of nude mice xenograft tumor of human hepatocellular carcinoma (HCC). MethodsThe transplanted SMMC-7721 cells were divided into SMMC-7721WT group (without treatment), SMMC-7721MAGL-KD group (with MAGL silencing), SMMC-7721MAGL-OE group (with MAGL overexpression), and SMMC-7721Vector group (transfected with empty vector). A total of 27 male BALB/c nude mice were randomly divided into group A (12 mice injected with the cells in the SMMC-7721WT group), group B (5 mice injected with the cells in the SMMC-7721MAGL-KD group), group C (5 mice injected with the cells in the SMMC-7721MAGL-OE group), and group D (5 mice injected with the cells in the SMMC-7721Vector group). The mice in group A were further divided into groups A1 (control group), A2 (treated with high-fat diet and JZL184, a specific inhibitor of MAGL), and A3 (fed with high-fat diet), with 4 mice in each group. The four groups were compared in terms of the change in tumor volume and the expression of proliferating cell nuclear antigen (PCNA), metal matrix proteinase-2 (MMP-2), lysophosphatidic acid (LPA), and prostaglandin E2 (PGE2) in tumor. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the SNK-q test was used for further comparison between two groups. ResultsThere was a significant difference in the relative protein expression of MAGL between the SMMC-7721WT group, the SMMC-7721MAGL-KD group, and the SMMC-7721MAGL-OE group (0.377±0.026 vs 0.182±0.055 vs 0.689±0.019, F=33.382, P<0.001); compared with the SMMC-7721WT group, the SMMC-7721MAGL-KD group had significantly lower protein expression of MAGL and the SMMC-7721MAGL-OE group had significantly higher expression (P<0.05). There was a significant difference in the size of subcutaneous xenograft tumor between groups A, B, C, and D (4236.125±1284.283 mm3 vs 1883.375±552.977 mm3 vs 10 146.061±1842.264 mm3 vs 4307452±2070.708 mm3, F=6.804, P=0.023). Group C had a lower growth rate of subcutaneous xenograft tumor than group A (P<005), and group B had a higher growth rate than group A (P<0.05). There were significant differences between groups A, B, and C in the levels of PCNA (25 843.821±4201.310 vs 17 426.95±5139.202 vs 39 753.103±5721.444, F=21.482, P<0.001) and MMP-2 (52 841.621±4339.253 vs 35 511.451±8251.423 vs 68 274.731±6418.594, F=11.526, P<0.001); group B had significantly lower levels of PCNA and MMP-2 than group A (P<0.05), and group C had significantly higher levels than group A (P<0.05). There was a significant difference in tumor volume between groups A1, A2, and A3 (23 476.289±483.872 mm3 vs 18 593.851±1385.805 mm3 vs 37 703.198±2925.254 mm3, F=47.371, P=0.004). Compared with group A1, group A3 had a significantly higher growth rate of subcutaneous xenograft tumor (P<0.05) and group A2 had a significantly lower growth rate (P<0.05). There was a significant difference in the level of PGE2 between groups A1, A2, and A3 (0.109±0.023 μmol/L vs 0.056±0.010 μmol/L vs 0.168±0.024 μmol/L, F=16492, P<0.001); group A3 had a significantly higher level of PGE2 than group A1 (P<0.05), and group A2 had a significantly lower level than group A1 (P<0.05). There was a significant difference in the level of PGE2 between groups B, C, and D (0.069±0.025 μmol/L vs 0.175±0.023 μmol/L vs 0.096±0.019 μmol/L, F=31.550, P<0.001); group B had a significantly lower level of PGE2 than group D (P<0.05), and group C had a significantly higher level than group D (P<0.05). ConclusionMAGL can promote the growth of subcutaneous xenograft tumor of HCC by regulating PGE2, suggesting that MAGL might become a potential target for HCC treatment in future.
【关键字】:癌, 肝细胞;单酰基甘油酯脂酶类;小鼠, 近交BALB C
【Key words】:carcinoma, hepatocellular; monoacylglycerol lipases;mice, inbred BALB C
【引证本文】:YU JJ, ZHANG JY, FAN DQ. Influence of monoacylglycerol lipase on growth of nude mice xenograft tumor of human hepatocellular carcinoma and related mechanism[J]. J Clin Hepatol, 2019, 35(7): 1525-1531. (in Chinese)
余家建, 张俊勇, 范德庆. 单酰甘油脂肪酶对人肝细胞癌裸鼠移植瘤的影响及其机制[J]. 临床肝胆病杂志, 2019, 35(7): 1525-1531.

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