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Published on: July 30, 2018
Transforming growth factor-β gene silencing using adenovirus expressing TGF-β1 or TGF-β2 shRNA
1Institute for Cancer Research, College of Medicine, Yonsei University, Seoul, South Korea.
Abstract:
Tumor cells secrete a variety of cytokines to outgrow and evade host immune surveillance. In this context, transforming growth factor-β1 (TGF-β1) is an extremely interesting cytokine because it has biphasic effects in cancer cells and normal cells. TGF-β1 acts as a growth inhibitor in normal cells, whereas it promotes tumor growth and progression in tumor cells. Overexpression of TGF-β1 in tumor cells also provides additional oncogenic activities by circumventing the host immune surveillance. Therefore, this study ultimately aimed to test the hypothesis that suppression of TGF-β1 in tumor cells by RNA interference can have antitumorigenic effects. However, we demonstrated here that the interrelation between TGF-β isotypes should be carefully considered for the antitumor effect in addition to the selection of target sequences with highest efficacy. The target sequences were proven to be highly specific and effective for suppressing both TGF-β1 mRNA and protein expression in cells after infection with an adenovirus expressing TGF-β1 short hairpin RNA (shRNA). A single base pair change in the shRNA sequence completely abrogated the suppressive effect on TGF-β1. Surprisingly, the suppression of TGF-β1 induced TGF-β3 upregulation, and the suppression of TGF-β2 induced another unexpected downregulation of both TGF-β1 and TGF-β3. Taken together, this information may prove useful when considering the design for a novel cancer immunogene therapy.
Insights
Suppression of transforming growth factor-β1 (TGF-β1) via RNA interference shows potential for cancer therapy. However, careful consideration of TGF-β isotype interactions is crucial for effective antitumorigenic effects.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Tumor cells utilize cytokines like transforming growth factor-β1 (TGF-β1) to promote growth and evade immune surveillance.
- TGF-β1 exhibits biphasic effects, inhibiting normal cell growth while promoting tumor progression and oncogenic activities.
Purpose of the Study:
- To investigate the antitumorigenic effects of suppressing TGF-β1 in tumor cells using RNA interference.
- To evaluate the specificity and efficacy of short hairpin RNA (shRNA) targeting TGF-β1.
- To explore the interrelations between TGF-β isotypes in the context of cancer immunotherapy.
Main Methods:
- Utilized an adenovirus vector to deliver TGF-β1 short hairpin RNA (shRNA) into tumor cells.
- Assessed the suppression of TGF-β1 mRNA and protein expression.
- Analyzed the impact of TGF-β1 suppression on other TGF-β isotypes (TGF-β2, TGF-β3).
Main Results:
- TGF-β1 shRNA effectively suppressed both TGF-β1 mRNA and protein expression, with high specificity.
- A single base pair mutation in the shRNA sequence abolished TGF-β1 suppression.
- Suppression of TGF-β1 led to an upregulation of TGF-β3.
- Suppression of TGF-β2 resulted in the downregulation of both TGF-β1 and TGF-β3.
Conclusions:
- RNA interference targeting TGF-β1 demonstrates potential for cancer immunotherapy.
- The interplay between TGF-β isotypes is critical and must be considered for designing effective cancer immunogene therapies.
- Further research into TGF-β isotype interactions is warranted for optimizing therapeutic strategies.
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