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IGF2BP3 enhances ferroptosis resistance in colon cancer by stabilizing SLC7A11 and is regulated by miR-98-5p
Yaya Sun1, Qingwei Liu1, Junjie Wu1
1School of Medicine, Southeast University, Nanjing, China.
Purpose:
Colon cancer remains a global health challenge with rising mortality, necessitating novel therapeutic strategies. IGF2BP3, an oncogenic RNA-binding protein, is implicated in colon cancer progression, while its role in ferroptosis regulation remains unclear. This study investigates IGF2BP3's role in ferroptosis regulation and its interplay with miR-98-5p in colon cancer, aiming to identify therapeutic targets for enhancing ferroptosis sensitivity.
Methods:
Bioinformatics analyses (TCGA, UALCAN, GEPIA) assessed IGF2BP3 expression and prognostic relevance in colon cancer. The expression of IGF2BP3 in clinical samples were analyzed via immunohistochemistry (IHC) and Western blotting. IGF2BP3-knockdown (KD) cell lines (HCT116/DLD-1) were generated using lentiviral shRNA. Ferroptosis sensitivity was evaluated via CCK-8 assays, MDA/ROS quantification, and rescue experiments with ferrostatin-1. Transcriptomic sequencing, RNA immunoprecipitation (RIP), and RNA stability assays identified IGF2BP3-regulated targets. Dual-luciferase reporter assays validated miR-98-5p-IGF2BP3 interactions. Xenograft models assessed in vivo tumor growth.
Results:
IGF2BP3 was significantly upregulated in colon cancer tissues and correlated with advanced T-stage, higher clinical stage, and poor survival (p<0.05). Knockdown of IGF2BP3 enhanced erastin-induced ferroptosis sensitivity, marked by elevated MDA and ROS levels, reversible by ferrostatin-1. Mechanistically, IGF2BP3 stabilized SLC7A11 mRNA via direct binding and SLC7A11 overexpression rescued ferroptosis resistance in IGF2BP3-KD cells. miR-98-5p directly targeted IGF2BP3's 3'-UTR, suppressing its expression and enhancing ferroptosis sensitivity. In vivo, IGF2BP3-KD suppressed tumor growth and reduced Ki67/SLC7A11 expression.
Conclusion:
IGF2BP3 drives ferroptosis resistance in colon cancer by stabilizing SLC7A11 mRNA, while miR-98-5p antagonizes this pathway via IGF2BP3 downregulation. Targeting the miR-98-5p/IGF2BP3/SLC7A11 axis offers a promising therapeutic strategy to enhance ferroptosis sensitivity and improve colon cancer outcomes.
Insights
Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) promotes colon cancer by resisting ferroptosis. Inhibiting IGF2BP3 with miR-98-5p enhances ferroptosis sensitivity, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Colon cancer presents a significant global health burden with increasing mortality.
- Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is an oncogenic protein implicated in colon cancer progression.
- The role of IGF2BP3 in ferroptosis regulation within colon cancer is not well understood.
Purpose of the Study:
- To investigate the role of IGF2BP3 in regulating ferroptosis in colon cancer.
- To explore the interplay between IGF2BP3 and miR-98-5p in colon cancer.
- To identify potential therapeutic targets for enhancing ferroptosis sensitivity in colon cancer.
Main Methods:
- Bioinformatic analyses (TCGA, UALCAN, GEPIA) and clinical sample analysis (IHC, Western blotting) assessed IGF2BP3 expression and prognosis.
- IGF2BP3 knockdown (KD) cell lines were generated, and ferroptosis sensitivity was evaluated using CCK-8 assays and MDA/ROS quantification.
- Transcriptomic sequencing, RNA immunoprecipitation (RIP), RNA stability assays, and dual-luciferase reporter assays elucidated molecular mechanisms and interactions.
Main Results:
- IGF2BP3 was upregulated in colon cancer, correlating with advanced stage and poor survival.
- IGF2BP3 knockdown enhanced ferroptosis sensitivity, evidenced by increased MDA and ROS levels.
- IGF2BP3 stabilized SLC7A11 mRNA, promoting ferroptosis resistance, while miR-98-5p suppressed IGF2BP3, enhancing ferroptosis.
Conclusions:
- IGF2BP3 drives ferroptosis resistance in colon cancer by stabilizing SLC7A11 mRNA.
- miR-98-5p antagonizes IGF2BP3, thereby increasing ferroptosis sensitivity.
- The miR-98-5p/IGF2BP3/SLC7A11 axis represents a promising therapeutic target for improving colon cancer treatment outcomes.
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