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Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
SIAH1-mediated RPS3 ubiquitination contributes to chemosensitivity in epithelial ovarian cancer
Lu Chen1,2, Wujiang Gao1,2, Chunli Sha1,2
1Reproductive Medicine Center, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
Abstract:
The E3 ligase SIAH1 is deregulated in human cancers and correlated with poor prognosis, but its contributions to chemoresistance in epithelial ovarian cancer (EOC) are not evident. Herein we found that SIAH1 was decreased in EOC tumour tissues and cell lines and negatively correlated with the RPS3 levels. SIAH1 overexpression suppressed tumour cell growth, colony formation, invasion, metastasis, and cisplatin resistance in vivo and in vitro. SIAH1 promoted RPS3 ubiquitination and degradation using the RING-finger domain, and these steps were required for RPS3 localization to the cytoplasm, which led to subsequent NF-κB inactivation and thereby conferred chemosensitivity. Moreover, ectopic expression of RPS3 or depletion of RPS3 ubiquitination mediated by SIAH1 via the K214R mutant significantly impaired cisplatin-induced tumour suppression in cells stably expressing SIAH1. Together, our findings reveal a tumour suppressor function of SIAH1 and provide evidence showing that the SIAH1-RPS3-NF-κB axis may act as an appealing strategy for tackling treatment resistance in EOC.
Insights
The E3 ligase SIAH1 suppresses epithelial ovarian cancer (EOC) growth and chemoresistance by degrading RPS3, leading to NF-κB inactivation. This SIAH1-RPS3-NF-κB pathway offers a potential strategy for overcoming EOC treatment resistance.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The E3 ligase SIAH1 is implicated in various cancers, but its role in epithelial ovarian cancer (EOC) chemoresistance remains unclear.
- SIAH1 deregulation is linked to poor prognosis in human cancers, necessitating investigation into its specific functions in EOC.
Purpose of the Study:
- To investigate the role of SIAH1 in epithelial ovarian cancer (EOC) and its impact on chemoresistance.
- To elucidate the molecular mechanism by which SIAH1 influences EOC progression and sensitivity to chemotherapy.
Main Methods:
- Quantitative analysis of SIAH1 and RPS3 levels in EOC tissues and cell lines.
- In vitro and in vivo experiments assessing the effects of SIAH1 overexpression on EOC cell behavior and tumor growth.
- Biochemical assays to determine the interaction between SIAH1 and RPS3, including ubiquitination and degradation studies.
- Analysis of NF-κB pathway activation and its modulation by the SIAH1-RPS3 axis.
Main Results:
- SIAH1 expression was decreased in EOC tissues and cell lines, correlating negatively with RPS3 levels.
- SIAH1 overexpression inhibited EOC cell growth, invasion, metastasis, and cisplatin resistance both in vitro and in vivo.
- SIAH1 promoted RPS3 ubiquitination and degradation, facilitating RPS3 cytoplasmic localization and subsequent NF-κB inactivation, thereby enhancing chemosensitivity.
- Ectopic RPS3 expression or impaired SIAH1-mediated ubiquitination counteracted the anti-tumor and chemosensitizing effects of SIAH1.
Conclusions:
- SIAH1 functions as a tumor suppressor in epithelial ovarian cancer.
- The SIAH1-RPS3-NF-κB signaling axis plays a critical role in regulating EOC chemoresistance.
- Targeting the SIAH1-RPS3-NF-κB pathway presents a promising therapeutic strategy for overcoming treatment resistance in EOC.
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