期刊
GENE THERAPY
卷 28, 期 7-8, 页码 422-434出版社
SPRINGERNATURE
DOI: 10.1038/s41434-020-0140-1
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资金
- Public Health Service from the National Institutes of Health [R01 HL-097088, R41 AI-122735, R21 EB-015684]
- Children's Miracle Network
- Kitzman Foundation
- International Postdoctoral Exchange Fellowship Program 2018 by the Office of China Postdoctoral Council
In vitro, AAV3-miR-26a and scAAV3-miR-122 vectors show moderate growth inhibition of Huh7 cells, with an additive effect when co-transduced. In vivo, the combination of these vectors leads to significant growth inhibition of Huh-derived human liver tumors in a mouse xenograft model.
We have previously reported that recombinant adeno-associated virus serotype 3 (AAV3) vectors transduce human liver tumors more efficiently in a mouse xenograft model following systemic administration. Others have utilized AAV8 vectors expressing miR-26a and miR-122 to achieve near total inhibition of growth of mouse liver tumors. Since AAV3 vectors transduce human hepatic cells more efficiently than AAV8 vectors, in the present studies, we wished to evaluate the efficacy of AAV3-miR-26a/122 vectors in suppressing the growth of human hepatocellular carcinoma (HCC) cells in vitro, and human liver tumors in a mouse model in vivo. To this end, a human HCC cell line, Huh7, was transduced with various multiplicities of infection (MOIs) of AAV3-miR-26a or scAAV3-miR-122 vectors, or both, which also co-expressed a Gaussia luciferase (GLuc) reporter gene. Only a modest level of dose-dependent growth inhibition of Huh7 cells (similar to 12-13%) was observed at the highest MOI (1 x 10(5) vgs/cell) with each vector. When Huh7 cells were co-transduced with both vectors, the extent of growth inhibition was additive (similar to 26%). However, AAV3-miR-26a and scAAV3-miR-122 vectors led to similar to 70% inhibition of growth of Huh-derived human liver tumors in a mouse xenograft model in vivo. Thus, the combined use of miR-26a and scAAV3-miR-122 delivered by AAV3 vectors offers a potentially useful approach to target human liver tumors.
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