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Published on: August 23, 2019
Inhibition of growth of human hepatoma cells by dual-function antisense IL-6 oligonucleotides
Naoki Kumagai1, Kanji Tsuchimoto, Satoshi Tsunematsu
1Department of Internal Medicine, Research Center for Liver Disease, Kitasato Institute Hospital, 5-9-1 Shirokane, Minato-ku, 108-8642, Tokyo, Japan
Abstract:
Hepatocellular lineage cell lines (two hepatoma and Chang liver cell lines) were found to produce interleukin-6 (IL-6). As the human hepatoma cell line, HCC-M expresses mRNA for both IL-6 and IL-6 receptor, we examined the possibility that IL-6 acted as an autocrine growth factor for HCC-M cells using two IL-6 antisense oligonucleotides (AS-1 and AS-2 oligomers) which were synthesized from different regions of an IL-6 cDNA clone. Both IL-6 antisense oligonucleotides inhibited the growth of HCC-M cells within 48 h (% inhibition by AS-1 and AS-2 oligomers was 53 and 21%, respectively). Although inhibition of HCC-M cell growth induced by AS-2 oligomer was restored by addition of exogenous recombinant IL-6 (rIL-6), the inhibition of growth induced by AS-1 oligomer was not fully restored by exogenous rIL-6, implicating the involvement of a nonantisense mechanism associated with four contiguous guanosine residues in this sequence. The inhibitory effect of AS-2 oligomer was attenuated after 72 h (% inhibition was 8%), whereas the AS-1 oligomer-induced inhibition of growth was sustained beyond 72 h (% inhibition was 38--39%). Therefore, these dual-function oligonucleotides that act via both an antisense and nonantisense mechanism may be of potential therapeutic value against hepatoma.
Insights
Hepatocellular carcinoma (HCC) cells produce interleukin-6 (IL-6), which promotes their growth. Dual-function antisense oligonucleotides targeting IL-6 show potential for hepatoma treatment by inhibiting cell proliferation.
Area of Science:
- Hepatology and Molecular Biology
- Cancer Research
- Immunology
Background:
- Hepatocellular lineage cells, including hepatoma cell lines, produce interleukin-6 (IL-6).
- The human hepatoma cell line HCC-M expresses mRNA for both IL-6 and its receptor, suggesting autocrine signaling.
- Interleukin-6 (IL-6) is implicated as a potential autocrine growth factor in hepatocellular carcinoma (HCC).
Purpose of the Study:
- To investigate the role of IL-6 as an autocrine growth factor in HCC-M cells.
- To evaluate the therapeutic potential of IL-6 antisense oligonucleotides against hepatoma.
Main Methods:
- Synthesis and application of two IL-6 antisense oligonucleotides (AS-1 and AS-2) derived from an IL-6 cDNA clone.
- Assessment of cell growth inhibition in HCC-M cells treated with antisense oligonucleotides.
- Evaluation of the effect of exogenous recombinant IL-6 (rIL-6) on oligonucleotide-induced growth inhibition.
Main Results:
- Both AS-1 and AS-2 oligonucleotides significantly inhibited HCC-M cell growth within 48 hours.
- Growth inhibition by AS-2 was reversible with exogenous rIL-6, indicating an antisense mechanism.
- Growth inhibition by AS-1 was sustained and not fully reversed by rIL-6, suggesting a dual (antisense and nonantisense) mechanism.
- The AS-1 oligonucleotide demonstrated sustained inhibition beyond 72 hours, unlike the AS-2 oligonucleotide.
Conclusions:
- IL-6 acts as an autocrine growth factor for HCC-M cells.
- Dual-function oligonucleotides, like AS-1, exhibiting both antisense and nonantisense activity, hold promise for hepatoma therapy.
- Targeting IL-6 through novel oligonucleotide mechanisms may offer a new therapeutic strategy for hepatocellular carcinoma.
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