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Tumor suppressor miR-424-5p abrogates ferroptosis in ovarian cancer through targeting ACSL4
Lin-Lin Ma1, Lin Liang1, Dan Zhou1
1Department of Gynecology and Obstetrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
Abstract:
Ovarian cancer is the most lethal gynecological cancer. In spite of recent advances, clinical outcomes remain poor, urgently needing novel therapeutic approaches. Growing evidence indicates that microRNAs play crucial roles in ovarian carcinogenesis and progression and that ferroptosis serves as a novel tumor suppressor. However, the molecular mechanisms of miRNA-mediated ferroptosis regulation in ovarian cancer are still largely unknown. In the present study, we show that miR-424-5p negatively regulates ferroptosis by directly targeting ACSL4 in ovarian cancer cells. Upregulation of miR-424-5p suppressed ACSL4 by directly binding to its 3'-UTR, which subsequently reduced erastin- and RSL3-induced ferroptosis. Meanwhile, knockdown of miR-424-5p increased the sensitivity of ovarian cancer cells to erastin and RSL3. Furthermore, ACSL4 was upregulated in ovarian cancer tissues, and high ACSL4 expression predicted worse prognosis and sensitized ovarian cancer cells to erastin- and RSL3-induced ferroptosis. Importantly, decreases in lipid peroxides and ferroptotic cell death mediated by miR-424-5p could be abrogated by ACSL4 overexpression. Taken together, our findings demonstrate that miR-424-5p regulates ferroptosis by targeting ACSL4 in ovarian cancer cells and suggest a potential therapeutic approach for ovarian cancer.
Insights
MicroRNA miR-424-5p suppresses ferroptosis in ovarian cancer by targeting ACSL4. This finding reveals a new mechanism for ovarian cancer progression and suggests potential therapeutic strategies targeting microRNAs and ferroptosis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Ovarian cancer remains a leading cause of gynecological cancer mortality, necessitating novel therapeutic strategies.
- MicroRNAs (miRNAs) are implicated in ovarian cancer development and progression.
- Ferroptosis, a form of regulated cell death, acts as a tumor suppressor, but its miRNA-mediated regulation in ovarian cancer is poorly understood.
Purpose of the Study:
- To elucidate the molecular mechanisms of miRNA-mediated ferroptosis regulation in ovarian cancer.
- To investigate the role of miR-424-5p in ferroptosis and its direct target in ovarian cancer cells.
Main Methods:
- Investigated the direct targeting of ACSL4 by miR-424-5p in ovarian cancer cells.
- Assessed the impact of miR-424-5p modulation on ferroptosis induced by erastin and RSL3.
- Analyzed ACSL4 expression in ovarian cancer tissues and correlated it with patient prognosis and ferroptosis sensitivity.
Main Results:
- miR-424-5p directly targets the 3'-UTR of ACSL4, leading to its suppression.
- Upregulation of miR-424-5p reduced erastin- and RSL3-induced ferroptosis, while its knockdown increased sensitivity.
- ACSL4 was upregulated in ovarian cancer tissues, associated with poor prognosis, and mediated ferroptosis sensitivity.
Conclusions:
- miR-424-5p negatively regulates ferroptosis in ovarian cancer by targeting ACSL4.
- The miR-424-5p/ACSL4 axis represents a novel regulatory pathway in ovarian cancer progression.
- Targeting this pathway offers a potential therapeutic avenue for ovarian cancer treatment.
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