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Interferon-Inducible Mx Promoter-Driven, Long-Term Transgene Expression System of Interferon-β for Cancer Gene
Atsushi Hamana1, Yuki Takahashi1, Makiya Nishikawa1
1Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University , Kyoto, Japan .
Abstract:
Gene therapy techniques aiming to induce the long-term interferon-β (IFN-β) expression are desirable for inhibiting cancer growth. However, there has been no success in this regard because IFN-β significantly inhibits transgene expression. This study used the IFN-inducible Mx promoter to promote IFN-β expression. The pMx-IFN-β plasmid was constructed to achieve long-term IFN-β expression. In cultured cells transfected with the Mx promoter-driven reporter protein plasmid, IFN-β induced concentration-dependent expression of the reporter protein. After the hydrodynamic injection of pMx-IFN-β into mice, the serum concentration of IFN-β was maintained at ≥100 pg/mL for >1 month. IFN-β expression was significantly suppressed by the co-injection of small interfering RNA targeting the interferon-α/β receptor (IFNAR), suggesting that IFN-β binding to IFNAR increased IFN-β expression. Moreover, the hydrodynamic injection of pMx-IFN-β significantly suppressed the growth of colon26 tumors in mice. In contrast, a conventional promoter-driven plasmid was less effective than pMx-IFN-β in all the experiments. Taken together, these results indicate that the interferon-inducible Mx promoter-driven expression system effectively achieves long-term expression of IFN-β and represents a potential tool for cancer gene therapy.
Insights
This study developed a novel gene therapy using the interferon-inducible Mx promoter for sustained interferon-beta (IFN-β) expression, effectively inhibiting tumor growth in mice.
Area of Science:
- Biotechnology
- Molecular Biology
- Cancer Research
Background:
- Long-term interferon-beta (IFN-β) expression is a promising strategy for cancer gene therapy.
- Previous attempts have been hindered by IFN-β's inhibition of transgene expression.
Purpose of the Study:
- To develop a gene therapy system for sustained IFN-β expression using an IFN-inducible promoter.
- To evaluate the efficacy of this system in vitro and in vivo for cancer treatment.
Main Methods:
- Constructed a pMx-IFN-β plasmid utilizing the IFN-inducible Mx promoter.
- Transfected cultured cells and performed hydrodynamic injection in mice.
- Co-injected small interfering RNA targeting the interferon-α/β receptor (IFNAR) to investigate feedback mechanisms.
Main Results:
- The Mx promoter enabled sustained IFN-β serum concentrations (≥100 pg/mL) for over a month in mice.
- IFN-β expression was found to be dependent on IFNAR signaling.
- pMx-IFN-β significantly suppressed colon26 tumor growth, outperforming a conventional promoter.
Conclusions:
- The interferon-inducible Mx promoter system achieves effective long-term IFN-β expression.
- This system shows significant potential as a tool for cancer gene therapy.
