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Published on: March 29, 2019
Generation of an inducible mouse model to reversibly silence Stat3
Mariah G Alorro1, Thomas P Pierce1, Moritz F Eissmann1
1Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, Victoria, 3084, Australia.
Abstract:
Signal transducer and activator of transcription 3 (Stat3) is a transcription factor that has many essential roles during inflammation, development and cancer. Stat3 is therefore an attractive therapeutic target in many diseases. While current Stat3 knockout mouse models led to a better understanding of the role of Stat3, the irreversible nature of Stat3 ablation does not model the effects of transient Stat3 therapeutic inhibition, and does not inform on potential dosage effects of Stat3. Using RNAi technology, we have generated a new mouse model allowing the inducible and reversible silencing of Stat3 in vivo, which mirrors the effects of specific Stat3 therapeutic interference. We showed that upon Doxycycline-mediated activation of the Stat3 short-hairpin RNA, Stat3 expression was efficiently reduced by about 80% in multiple organs and cell types. Moreover, Stat3 reduction was sufficient to reduce tumor burden in a clinically-validated mouse model of gastric cancer. Finally, we demonstrated that Stat3 silencing during embryonic development led to reduced birth rate without leading to complete embryonic lethality, in contrast to full Stat3 ablation. In conclusion, this new mouse model will be invaluable to understand the effects of Stat3 therapeutic interference and Stat3 dosage effects.
Insights
A new inducible and reversible Stat3 mouse model aids study of transient therapeutic inhibition. This model effectively reduces tumor burden and reveals developmental effects without lethality, advancing Stat3 research.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- Signal transducer and activator of transcription 3 (Stat3) is crucial in inflammation, development, and cancer.
- Targeting Stat3 is a promising therapeutic strategy for various diseases.
- Existing Stat3 knockout models do not replicate transient or dose-dependent therapeutic inhibition.
Purpose of the Study:
- To develop a novel mouse model for inducible and reversible Stat3 silencing in vivo.
- To investigate the effects of transient Stat3 inhibition on cancer and embryonic development.
- To enable the study of Stat3 dosage effects in therapeutic contexts.
Main Methods:
- Generation of a mouse model utilizing RNAi for inducible and reversible Stat3 knockdown.
- Administration of Doxycycline to activate Stat3 short-hairpin RNA expression.
- Assessment of Stat3 expression reduction in various organs and cell types.
- Evaluation of tumor burden in a gastric cancer model.
- Analysis of Stat3 silencing effects during embryonic development.
Main Results:
- Stat3 expression was reduced by approximately 80% in multiple tissues upon Doxycycline induction.
- Stat3 reduction significantly decreased tumor burden in a gastric cancer mouse model.
- Inducible Stat3 silencing during embryonic development resulted in reduced birth rates but not embryonic lethality.
Conclusions:
- The developed mouse model accurately mimics transient Stat3 therapeutic interference.
- This model is valuable for studying Stat3's role in cancer and development with adjustable inhibition.
- It provides a platform for exploring Stat3 dosage effects in disease treatment and developmental biology.
