Targeted tumor gene therapy based on loss of IGF2 imprinting

摘要

Loss of imprinting (LOI) of the insulin-like growth factor 2 gene (IGF2) is one of the most common epigenetic abnormalities seen in human neoplasms. LOI may be associated with the lack of Zinc-finger DNA binding protein CTCF-mediated enhancer insulation, presumably due to the gain of methylation on the maternal allele of the differentially methylated domain (DMD) of the imprinting control region. This results in an interaction between the IGF2 promoters and enhancers; and IGF2 is produced from both alleles. In this study we investigated the feasibility of a novel anti-cancer adenovirus (AdDC312-DT-A) driven by H19 enhancer DMD-H19 promoter complex. Cell lines with IGF2 LOI (HCT-8, HT-29 and H-522) that were infected with AdDC312-EGFP produced the EGFP protein. However, in cells in which imprinting was maintained (MOI) (MCF-7 and GES-1), no EGFP protein was produced. The AdDC312-DT-A significantly decreased cell viability and induced apoptosis only in LOI cells in vitro, and suppressed tumour development in HCT-8 xenografts in nude mice. In conclusion, the toxin gene therapy proves effective in inhibiting LOI cell growth in vitro and in vivo and provides a novel option for targeted gene therapy based on loss of IGF2 imprinting.