Abstract
Targeted expression of gene technique is an important therapeutic strategy for lung cancer. MicroRNA-7 has been well documented as a promising tumor suppressor but never been test in specific gene-promoter-targeted expression in cancer gene therapy. Here, we first evaluated the efficacy of miR-7 expression operated by the promoter of TTF-1, a lineage-specific oncogene in lung cancer, in vitro using an eukaryotic vector of TTF-1-promoter-operated expression of miR-7 (termed as p-T-miR-7). Interestingly, using a nude mice model, the growth and metastasis of human lung cancer cells in vivo were significantly reduced in remote hypodermic injection of the p-T-miR-7 group, accompanied by increased expression of miR-7 and reduced transduction of the Akt and Erk pathway in situ. Mechanism aspect, global gene expression analysis showed that downregulation of NDUFA4, a novel target of miR-7, contributed to the effects of miR-7 expression operated by TTF-1 promoter on the growth and metastasis of human lung cancer cells, as well as altered transduction of the Akt and Erk pathway. Finally, there was no significant difference in weight or histopathology of other organs. These data provided a basis for development of novel modality of miRNA-based targeted expression therapy against clinical lung cancer.
Highlights
Lung cancer is one of the most common causes of cancer death
transcription factor (TTF)-1-Promoter-Operating miR-7 Expression Suppressed the Growth of Human Lung Cells In Vitro To investigate whether the TTF-1 promoter might be an ideal candidate for operating miR-7 expression in lung cancer, as shown in Figure 1A, we first amplified and inserted the sequence of both TTF-1 promoter and miR-7 into pGL3.0 basic vector and successfully constructed an eukaryotic expression vector, which could express miR-7 operated by TTF-1 promoter (Figure S1)
To observe the target efficiency, we further transfected the plasmid p-T-miR-7 into six different human cancer cell lines, including lung cancer cell line 95D cells, A549 cells, NCIH292 cells, gastric cancer cell line SGC901 cells, hepatitic cancer cell line HepG2 cells, and colon cancer cell line SW620 cells, and detected the expression level of miR-7 operated by TTF-1 promoter
Summary
Lung cancer is one of the most common causes of cancer death. The overall 5-year survival rates for surgical resection in lung cancer patients still remain poor. It is important to identify and characterize new molecular markers and genes to develop more targeted treatment strategies to improve the clinical outcome of lung cancer.[1,2,3] Recent evidence showed that the technique of targeted gene expression, including specific gene-promoter-operating expression and distinct delivery systems, is a crucial strategy for gene therapy against various cancers including lung cancer.[4,5,6,7] And, microRNAs (miRNAs), which are endogenous 21- to 23-nt non-coding RNAs, have pointed to central regulatory roles in the development of lung cancer and emerged as important targets for gene therapy against clinical lung cancer.[8,9,10,11] This research suggested that targeted expression of distinct miRNA molecules might be a useful therapeutic strategy for lung cancer, which would be benefit to the outcome of clinical lung cancer patients
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