A methylated oligonucleotide inhibits IGF2 expression and enhances survival in a model of hepatocellular carcinoma
Xiaoming Yao, … , Tao Li, Andrew R. Hoffman
Xiaoming Yao, … , Tao Li, Andrew R. Hoffman
Published January 15, 2003
Citation Information: J Clin Invest. 2003;111(2):265-273. https://doi.org/10.1172/JCI15109.
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Article Genetics

A methylated oligonucleotide inhibits IGF2 expression and enhances survival in a model of hepatocellular carcinoma

Abstract

IGF-II is a mitogenic peptide that has been implicated in hepatocellular oncogenesis. Since the silencing of gene expression is frequently associated with cytosine methylation at cytosine-guanine (CpG) dinucleotides, we designed a methylated oligonucleotide (MON1) complementary to a region encompassing IGF2 promoter P4 in an attempt to induce DNA methylation at that locus and diminish IGF2 mRNA levels. MON1 specifically inhibited IGF2 mRNA accumulation in vitro, whereas an oligonucleotide (ON1) with the same sequence but with nonmethylated cytosines had no effect on IGF2 mRNA abundance. MON1 treatment led to the specific induction of de novo DNA methylation in the region of IGF2 promoter hP4. Cells from a human hepatocellular carcinoma (HCC) cell line, Hep 3B, were implanted into the livers of nude mice, resulting in the growth of large tumors. Animals treated with MON1 had markedly prolonged survival as compared with those animals treated with saline or a truncated methylated oligonucleotide that did not alter IGF2 mRNA levels in vitro. This study demonstrates that a methylated sense oligonucleotide can be used to induce epigenetic changes in the IGF2 gene and that inhibition of IGF2 mRNA accumulation may lead to enhanced survival in a model of HCC.

Authors

Xiaoming Yao, Ji-Fan Hu, Mark Daniels, Hadas Shiran, Xiangjun Zhou, Huifan Yan, Hongqi Lu, Zhilan Zeng, Qingxue Wang, Tao Li, Andrew R. Hoffman

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Figure 7

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Cumulative survival rate of nude mice implanted with Hep 3B tumor cells....
Cumulative survival rate of nude mice implanted with Hep 3B tumor cells. (a) In study 1, athymic nude mice were implanted with Hep 3B tumor cells (107 cells). Ten days after tumor cell implantation, animals were randomly assigned into treatment groups and began to receive MON1 at doses of 0.7 mg/kg and 7 mg/kg and PBS control. Animals were dosed intravenously through the tail vein twice a week. At the end of the study, animals receiving MON1 treatment (7 mg/kg) had significantly prolonged survival in a clear dose-dependent manner (P < 0.05 by the Mantel-Cox log-rank test).(b) In study 2, nude mice were implanted with 107 Hep 3B cells. Four weeks after implantation, animals were randomly assigned to receive MON2 (10 mg/kg, n = 13) or MON1 (10 mg/kg, n = 13). All treatments were administered through tail-vein injection twice a week. The Mantel-Cox log-rank test shows a significantly prolonged survival in animals receiving MON1 treatment (10 mg/kg) as compared with those receiving MON2 treatment (P < 0.05).