Cationic liposome mediated delivery of FUS1 and hIL-12 coexpression plasmid demonstrates enhanced activity against human lung cancer.
Cationic liposome mediated delivery of FUS1 and hIL-12 coexpression plasmid demonstrates enhanced activity against human lung cancer.
复制标题
阳离子脂质体介导的 FUS1 和 hIL-12 共表达质粒的递送显示出增强的抗人肺癌活性。
DOI：
10.2174/1568009614666140113115651
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发表时间：
2014
影响因子：
3
通讯作者：
Yuquan Wei
中科院分区：
文献类型：
--
作者：
Jiang Ren;Chuanjiang Yu;Shifei Wu;F. Peng;Q. Jiang;Xue;Guo;Hua;Xiang Chen;Xiaolan Su;Xinmei Luo;Wen Zhu;Yuquan Wei
FUS 1是肺癌中最重要的抑癌基因之一，也是一种重要的免疫调节分子。白细胞介素（IL）-12作为一种潜在的抗肿瘤细胞因子引起了人们的极大兴趣。阳离子脂质体已被证明可以有效地将治疗基因输送到肺部，并在静脉内给药时控制转移性肺肿瘤。本研究采用HuPBL-NOD/SCID小鼠模型，评价阳离子脂质体介导的FUS 1和人IL（hIL）-12真核共表达质粒（pVITRO 2-FUS 1-hIL-12）局部和全身给药对人肺癌的增效作用，并探讨其分子机制。本研究表明，FUS 1-hIL-12共表达能更充分地抑制肿瘤生长和实验性肺转移，显著延长实验性肺转移小鼠的生存期。与顺铂相比，FUS 1-hIL-12共表达对实验性肺转移瘤的抑制活性更高，毒性更低。结果表明，FUS 1-hIL-12共表达能显著提高人γ干扰素（hIFN-γ）和hIL-15的分泌水平，增强MHC-Ⅰ和Fas的表达，增加活化的人CD 4+和CD 8 + T淋巴细胞的浸润，从而诱导抗肿瘤免疫应答。FUS 1-hIL-12共表达可明显诱导肿瘤细胞凋亡，抑制肿瘤细胞增殖，其机制可能与STAT 1信号通路的激活和p53的上调有关。此外，FUS 1-hIL-12共表达还显著减少肿瘤中的血管生成，这可能与VEGF和VEGFR的下调以及人IP-10的上调有关。因此，我们的研究结果表明，阳离子脂质体介导的FUS 1-hIL-12的共表达可能是一个新的有前途的策略，肺癌的治疗在临床研究。
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.