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SQLE Knockdown inhibits bladder cancer progression by regulating the PTEN/AKT/GSK3β signaling pathway through P53
Fan Zou1, Wu Chen1, Tianbao Song1
1Department of Urology, Renmin Hospital of Wuhan University, 99 ziyang road, Wuhan, 430060, Hubei Province, China.
Abstract:
Bladder cancer (BCa) is one of the most common malignancies worldwide. However, the lack of accurate and effective targeted drugs has become a major problem in current clinical treatment of BCa. Studies have demonstrated that squalene epoxidase (SQLE), as a key rate-limiting enzyme in cholesterol biosynthesis, is involved in cancer development. In this study, our analysis of The Cancer Genome Atlas, The Genotype-Tissue Expression, and Gene Expression Omnibus databases showed that SQLE expression was significantly higher in cancer tissues than it was in adjacent normal tissues, and BCa tissues with a high SQLE expression displayed a poor prognosis. We then confirmed this result in qRT-PCR and immunohistochemical staining experiments, and our vitro studies demonstrated that SQLE knockdown inhibited tumor cell proliferation and metastasis through the PTEN/AKT/GSK3β signaling pathway. By means of rescue experiments, we proved that that P53 is a key molecule in SQLE-mediated regulation of the PTEN/AKT/GSK3β signaling pathway. Simultaneously, we verified the above findings through a tumorigenesis experiment in nude mice. In conclusion, our study shows that SQLE promotes BCa growth through the P53/PTEN/AKT/GSK3β axis, which may serve as a therapeutic biological target for BCa.
Insights
Squalene epoxidase (SQLE) is upregulated in bladder cancer (BCa), correlating with poor prognosis. Inhibiting SQLE suppresses BCa growth and metastasis via the P53/PTEN/AKT/GSK3β pathway, offering a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Bladder cancer (BCa) is a prevalent malignancy with limited targeted therapies.
- Squalene epoxidase (SQLE), a key enzyme in cholesterol biosynthesis, is implicated in cancer progression.
- Identifying novel therapeutic targets for BCa is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the role of SQLE in bladder cancer development and progression.
- To elucidate the molecular mechanisms underlying SQLE's function in BCa.
- To evaluate SQLE as a potential therapeutic target for BCa.
Main Methods:
- Bioinformatic analysis of The Cancer Genome Atlas, The Genotype-Tissue Expression, and Gene Expression Omnibus databases.
- Quantitative reverse transcription PCR (qRT-PCR) and immunohistochemical staining.
- In vitro cell culture experiments (SQLE knockdown, rescue experiments) and in vivo tumorigenesis assays in nude mice.
Main Results:
- SQLE expression is significantly elevated in BCa tissues compared to normal tissues, associated with poor prognosis.
- SQLE knockdown inhibits BCa cell proliferation and metastasis.
- SQLE regulates the PTEN/AKT/GSK3β signaling pathway, with P53 identified as a key mediator.
Conclusions:
- SQLE promotes bladder cancer growth and metastasis through the P53/PTEN/AKT/GSK3β signaling axis.
- Targeting SQLE presents a promising therapeutic strategy for bladder cancer.
- This study identifies a novel molecular pathway critical for BCa pathogenesis.
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