title: Synergistic effects of eukaryotic coexpression plasmid carrying  LKB1 and FUS1 genes on lung cancer in vitro and in vivo.
abstract: OBJECTIVE
  LKB1 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.
  
  
  METHODS
  In this study, two kinds of tumor suppressor genes, LKB1 and FUS1, were constructed in an eukaryotic coexpression plasmid pVITRO(2), and then, we evaluated the synergistic effects of the two genes on anticancer activity and explored the relevant molecular mechanisms.
  
  
  RESULTS
  We 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: pVITRO(2)–LKB1–FUS1 complex (LPs–pVITRO(2)–LKB1–FUS1) into subcutaneous lung tumor xenograft resulted in more significant inhibition of tumor growth. Furthermore, intravenous injection of LPs–pVITRO(2)–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 tha tthe synergistic anti-lung cancer effects of coexpression ofLKB1 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.
  
  
  CONCLUSIONS
  Our 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.
authors.forename: Lingdong
authors.initials: L
authors.lastname: Li
authors.forename: Chuanjiang
authors.initials: C
authors.lastname: Yu
authors.forename: Jiang
authors.initials: J
authors.lastname: Ren
authors.forename: Sujuan
authors.initials: S
authors.lastname: Ye
authors.forename: Wenjing
authors.initials: W
authors.lastname: Ou
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Weihan
authors.initials: W
authors.lastname: Yang
authors.forename: Guoxing
authors.initials: G
authors.lastname: Zhong
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.forename: Huashan
authors.initials: H
authors.lastname: Shi
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Su
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
authors.forename: Wen
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000517:prevention & control / Q000556:secondary; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D004357:Drug Synergism; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C499993:TUSC2 protein, human; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases