Lentivirus-mediated RASSF1A expression suppresses aggressive phenotypes of gastric cancer cells in vitro and in vivo.
Lentivirus-mediated RASSF1A expression suppresses aggressive phenotypes of gastric cancer cells in vitro and in vivo.
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慢病毒介导的RASSF1A表达抑制体内外胃癌细胞的侵袭表型
DOI：
10.1038/gt.2015.49
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发表时间：
2015-10
期刊：
影响因子：
5.1
通讯作者：
Sun XJ
中科院分区：
文献类型：
--
作者：
Zhou PH;Zheng JB;Wei GB;Wang XL;Wang W;Chen NZ;Yu JH;Yao JF;Wang H;Lu SY;Sun XJ
Ras相关结构域家族蛋白1亚型A（RASSF 1A）表达的缺失与多种人类癌症的发生相关，并且癌胚抗原（CEA）的表达经常发生在胃癌中。本研究探讨了缺氧诱导CEA启动子驱动的RASSF 1A表达恢复对裸鼠异种移植瘤生长的影响，以及对胃癌细胞活力、细胞周期分布、凋亡、集落形成和侵袭能力的体外调节。数据显示，胃癌SGC 7901细胞中CEA mRNA和蛋白质的水平比第二种胃癌细胞系MKN 28或MCF-10A正常上皮乳腺细胞系中高得多。与阴性对照病毒感染的SGC 7910细胞相比，SGC 7901细胞中RASSF 1A表达恢复。RASSF 1A表达恢复显著抑制胃癌细胞的生存能力、集落形成和侵袭能力，但在体外诱导细胞周期阻滞和凋亡，尤其是在缺氧培养条件下。在基因水平上，缺氧培养条件下RASSF 1A表达的恢复显著抑制了基质金属蛋白酶-2的表达，并阻止了cyclinD 1的表达。裸鼠异种移植试验表明，RASSF 1A表达的恢复减少了胃癌异种移植物的形成和生长。总之，使用低氧诱导和CEA启动子驱动的载体恢复RASSF 1A表达抑制了体外和体内胃癌细胞的侵袭性表型。提示LV-5 HRE-CEAp-RASSF 1A基因治疗进展期胃癌可能是一种有前景的新方法。
Loss of Ras association domain family protein 1 isoform A (RASSF1A) expression is associated with the development of a variety of human cancers and the expression of carcinoembryonic antigen (CEA) frequently occurs in gastric cancer. This study investigated the effects of RASSF1A expression restoration using a hypoxia-inducible CEA promoter-driven vector on xenograft tumor growth in nude mice and on the in-vitro regulation of gastric cancer cell viability, cell cycle distribution, apoptosis, colony formation and invasion capacity. The data showed that the level of CEA mRNA and protein was much higher in gastric cancer SGC7901 cells than in a second gastric cancer cell line, MKN28, or in the MCF-10A normal epithelial breast cell line. RASSF1A expression was restored in SGC7901 cells compared with the negative control virus-infected SGC7910 cells. RASSF1A expression restoration significantly inhibited gastric cancer cell viability, colony formation and invasion capacity, but induced cell cycle arrest and apoptosis in vitro, especially under hypoxic culture conditions. At the gene level, restoration of RASSF1A expression under hypoxic culture conditions significantly suppressed matrix metalloproteinase-2 expression and prevented cyclinD1 expression. A nude mouse xenograft assay showed that the restoration of RASSF1A expression reduced gastric cancer xenograft formation and growth. In conclusion, the restoration of RASSF1A expression using a hypoxia-inducible and CEA promoter-driven vector suppressed aggressive phenotypes of gastric cancer cells in vitro and in vivo. These results suggest that LV-5HRE-CEAp-RASSF1A gene therapy may be a promising novel approach to treat advanced gastric cancer.