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Synergistic effects of eukaryotic coexpression plasmid carrying LKB1 and FUS1 genes on lung cancer in vitro and in vivo

  • Original article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

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 pVITRO2, 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: 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.

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.

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Abbreviations

LKB1:

Liver kinase B1

FUS1:

Tumor suppressor candidate 2

MMP:

Matrix metalloproteinase

NEDD9:

Neural precursor cell expressed, developmentally downregulated 9

PDGF:

Platelet-derived growth factor

PDGFR:

Platelet-derived growth factor receptor

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptors

p-p53:

Phosphorylated p53

p-mTOR:

Phosphorylated mammalian target of rapamycin

p-AMPK:

Phosphorylated adenosine monophosphate-activated protein kinase

p-FAK:

Phosphorylated focal adhesion kinase

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium bromide

H&E:

Hematoxylin and eosin

TUNEL:

TdT-mediated dUTP-X nick end labeling

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 81071863) and the National Science and Technology Major Projects of New Drugs (No. 2012ZX09103301-009). The authors thank for Mrs Yongqiu Mao (Chengdu, China) and Miss Xiaorong Huang (Chengdu, China) for technical support and Dr. Yang Wan (Chengdu, China) for statistical analysis.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 1, Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, Chengdu, 610041, Sichuan, People’s Republic of China

    Lingdong Li, Chuanjiang Yu, Jiang Ren, Sujuan Ye, Wenjing Ou, Yu Wang, Weihan Yang, Guoxing Zhong, Xiang Chen, Huashan Shi, Xiaolan Su, Lijuan Chen & Wen Zhu

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  1. Lingdong Li
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  2. Chuanjiang Yu
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  3. Jiang Ren
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  5. Wenjing Ou
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  6. Yu Wang
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  9. Xiang Chen
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  11. Xiaolan Su
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  12. Lijuan Chen
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  13. Wen Zhu
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Corresponding authors

Correspondence to Lijuan Chen or Wen Zhu.

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Lingdong Li and Chuanjiang Yu have contributed equally to this work.

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Li, L., Yu, C., Ren, J. et al. Synergistic effects of eukaryotic coexpression plasmid carrying LKB1 and FUS1 genes on lung cancer in vitro and in vivo. J Cancer Res Clin Oncol 140, 895–907 (2014). https://doi.org/10.1007/s00432-014-1607-5

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