Cationic Liposome Mediated Delivery of FUS1 and hIL-12 Coexpression Plasmid Demonstrates Enhanced Activity against Human Lung Cancer
Jiang Ren, Chuanjiang Yu, Shifei Wu, Feng Peng, Qianqian Jiang, Xuechao Zhang, Guoxing Zhong, Huashan Shi, Xiang Chen, Xiaolan Su, Xinmei Luo, Wen Zhu and Yuquan Wei
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FUS1 is one of the most important tumor suppressor genes in lung cancer, as well as an important
immunomodulatory molecule. Interleukin (IL)-12 has attracted considerable interest as a potential anti-tumor cytokine.
Cationic liposome has been shown to effectively deliver therapeutic genes to the lungs and control metastatic lung tumors
when administered intravenously. Here we evaluated the enhanced efficacy of cationic liposome-mediated delivery of
FUS1 and human IL (hIL)-12 eukaryotic coexpression plasmid (pVITRO2-FUS1-hIL-12) against the human lung cancer
in HuPBL-NOD/SCID mice model by local and systemic administration, and explored the related molecular mechanism.
Our study demonstrated that FUS1-hIL-12 coexpression could more sufficiently inhibit tumor growth and experimental
lung metastasis, significantly prolong the survival of experimental lung metastasis mice. Moreover, FUS1-hIL-12
coexpression performed higher antitumor activity and lower toxicity in the inhibition of experimental lung metastatic
tumor compared to cisplatin. We further identified that FUS1-hIL-12 coexpression could induce strong antitumor immune
response by secreting much higher levels of human interferon-γ (hIFN-γ) and hIL-15, enhancing expression of MHC-I
and Fas, increasing infiltration of activated human CD4+ and CD8+ T lymphocytes. FUS1-hIL-12 coexpression could
also obviously induce tumor cell apoptosis and inhibit tumor cell proliferation partly by higher activation of STAT1 signal
pathway and upregulation of p53. In addition, FUS1-hIL-12 coexpression also superiorly reduced the angiogenesis in
tumors, which might be associated with downregulation of VEGF and VEGFR, and upregulation of human IP-10. Our
results therefore suggest that cationic liposome-mediated FUS1-hIL-12 coexpression may be a new promising strategy for
lung cancer treatment in clinical studies.
Cationic liposome, FUS1-hIL-12 eukaryotic coexpression, Gene therapy, HuPBL-NOD/SCID, Lung cancer,
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Keyuan 4th Road, NO. 1, Gaopeng Street, High Technological Development Zone, Chengdu, Sichuan, 610041, P. R. China