Synergistic effects of eukaryotic coexpression plasmid carrying LKB1 and FUS1 genes on lung cancer in vitro and in vivo
Synergistic effects of eukaryotic coexpression plasmid carrying LKB1 and FUS1 genes on lung cancer in vitro and in vivo
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携带LKB1和FUS1基因的真核共表达质粒对肺癌体外和体内的协同作用
DOI：
10.1007/s00432-014-1607-5
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发表时间：
2014-06-01
影响因子：
3.6
通讯作者：
Zhu, Wen
中科院分区：
文献类型：
--
作者：
Li, Lingdong;Yu, Chuanjiang;Zhu, Wen
目的LKB 1和FUS 1是两种新的抑癌基因，也是肺癌的早期基因。近年来的研究表明，LKB 1和FUS 1在肺癌的发生发展过程中起重要作用。方法将两种抑癌基因LKB 1和FUS 1分别构建于真核共表达质粒pVITRO 2中，我们评估了这两个基因对抗癌活性的协同作用，并探讨了相关的分子机制。在体外可协同抑制肺癌细胞的生长、侵袭和迁移，诱导细胞凋亡，阻滞细胞周期。瘤内给药脂质体：pVITRO 2-LKB 1-FUS 1复合物（LPs-pVITRO 2-LKB 1-FUS 1）至皮下肺肿瘤异种移植物中导致更显著的肿瘤生长抑制。此外，将LPs-pVITRO 2-LKB 1-FUS 1静脉内注射到携带实验性A549肺转移的小鼠中，证明了转移性肿瘤结节数量的协同减少。最后，LKB 1和FUS 1联合治疗延长了肺肿瘤荷瘤小鼠的总生存期。进一步研究表明，LKB 1和FUS 1共表达的协同抗肺癌作用可能与上调p-p53、p-AMPK和下调p-mTOR、p-FAK、MMPs、NEDD 9、VEGF/R和PDGF/R有关。结论LKB 1和FUS 1共表达质粒联合治疗肺癌可能是一种新的有效的治疗策略。
PurposeLKB1 and FUS1 are two kinds of new tumor suppressor genes as well as early-stage genes in lung cancer. Recent studies showed that LKB1 and FUS1 play important roles in lung carcinogenesis process. We hypothesized that combined gene therapy with LKB1 and FUS1 could inhibit lung cancer growth and development synergistically.MethodsIn this study, two kinds of tumor suppressor genes, LKB1 and FUS1, were constructed in an eukaryotic coexpression plasmid pVITRO2, and then, we evaluated the synergistic effects of the two genes on anticancer activity and explored the relevant molecular mechanisms.ResultsWe defined coexpression of LKB1 and FUS1 could synergistically inhibited lung cancer cells growth, invasion and migration and induced the cell apoptosis and arrested cell cycle in vitro. Intratumoral administration of liposomes: pVITRO2–LKB1–FUS1 complex (LPs–pVITRO2–LKB1–FUS1) into subcutaneous lung tumor xenograft resulted in more significant inhibition of tumor growth. Furthermore, intravenous injection of LPs–pVITRO2–LKB1–FUS1 into mice bearing experimental A549 lung metastasis demonstrated synergistic decrease in the number of metastatic tumor nodules. Finally, combined treatment with LKB1 and FUS1 prolonged overall survival in lung tumor-bearing mice. Further study showed that the synergistic anti-lung cancer effects of coexpression of LKB1 and FUS1 might be related to upregulation of p-p53, p-AMPK and downregulation of p-mTOR, p-FAK, MMPs, NEDD9, VEGF/R and PDGF/R.ConclusionsOur results suggest that combined therapy with eukaryotic coexpression plasmid carrying LKB1 and FUS1 genes may be a novel and efficient treatment strategy for human lung cancer.