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miR-29a-5p modulates ferroptosis by targeting ferritin heavy chain FTH1 in prostate cancer
Guang Yang1, Qi Pan2, Yang Lu2
1Department of Urology Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR China; Central Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
Abstract:
Ferroptosis is a kind of regulatory necrosis caused by phospholipid iron-dependent peroxidation. MiRNAs are known to play key roles in diverse biological functions. However, the molecular basis of miRNA-mediated ferroptosis in prostate cancer has not been fully stated. Here, with TCGA prostate cancer miRNA-seq data, we utilized Multivariate Cox regression analysis to prioritize potential miRNA and validated it in vitro and in vivo. We identified miR-29a-5p by TCGA prostate cancer miRNA-seq dataset. And we confirmed the expression of miR-29a-5p in prostate cancer cell lines. MiR-29a-5p knockdown reduced proliferation in PC-3 and LNCaP cells while increased Fe2+ and malondialdehyde (MDA) levels, the opposite phenomenon was observed with miR-29a-5p overexpression. Luciferase reporter assay showed an interaction between miR-29a-5p and Nrf2 downstream gene FTH1, subsequent rescue experiments also indirectly proved their direct effect. Finally, suppression of miR-29a-5p effectively inhibited tumor growth in vivo. These findings proved that the important role of miR-29a-5p in prostate cancer ferroptosis.
Insights
MicroRNAs regulate ferroptosis, a cell death process, in prostate cancer. This study identifies miR-29a-5p as a key regulator, impacting tumor growth and ferroptosis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Ferroptosis, a regulated form of necrosis, is driven by iron-dependent lipid peroxidation.
- MicroRNAs (miRNAs) are crucial regulators of cellular processes, including cell death.
- The specific role of miRNAs in mediating ferroptosis within prostate cancer remains incompletely understood.
Purpose of the Study:
- To elucidate the molecular mechanisms of miRNA-mediated ferroptosis in prostate cancer.
- To identify specific miRNAs involved in regulating ferroptosis in prostate cancer.
- To investigate the therapeutic potential of targeting these miRNAs for prostate cancer treatment.
Main Methods:
- Utilized TCGA prostate cancer miRNA-seq data for bioinformatic analysis.
- Employed Multivariate Cox regression to identify significant miRNAs.
- Validated findings through in vitro cell line experiments (knockdown/overexpression) and in vivo tumor models.
- Conducted luciferase reporter assays and rescue experiments to confirm molecular interactions.
Main Results:
- Identified and validated miR-29a-5p as a key miRNA in prostate cancer ferroptosis.
- Demonstrated that miR-29a-5p knockdown inhibits proliferation and promotes ferroptosis markers (increased Fe2+, MDA).
- Showed that miR-29a-5p overexpression has opposing effects on proliferation and ferroptosis.
- Confirmed an interaction between miR-29a-5p and FTH1, a downstream target of Nrf2.
- In vivo studies confirmed that suppressing miR-29a-5p inhibits prostate cancer tumor growth.
Conclusions:
- MiR-29a-5p plays a significant role in regulating ferroptosis in prostate cancer.
- MiR-29a-5p influences prostate cancer cell proliferation and tumor growth.
- The miR-29a-5p/FTH1 axis is implicated in ferroptosis regulation within prostate cancer.
- Targeting miR-29a-5p represents a potential therapeutic strategy for prostate cancer.
