PTTG3P-miR-142-5p-IGF2BP3 axis governs ferroptosis in hepatocellular carcinoma.
Zhang Wenjuan, Liu Hao, Zhang Shuhan, Li Zhiyan, Shi Shifan, Lu Jiahui, Gao Yingmei, Sun Qiyu, Li Jian
Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) is resistant to therapy and carries high mortality. Ferroptosis is a promising therapeutic target in which long non-coding RNAs may be involved. This study aimed to investigate the regulatory role of the PTTG3P-miR-142-5p-IGF2BP3 axis in ferroptosis during HCC, revealing the potential mechanisms by which this axis influences HCC initiation and progression. METHODS: Bioinformatics analysis revealed the expression and prognostic significance of PTTG3P in HCC. Concurrently, overexpression and knockdown models of PTTG3P, miR-142-5p, and IGF2BP3 were established to detect intracellular levels of ferroptosis regulatory factors. Gene interactions were explored via western blot, quantitative real-time PCR, and luciferase reporter assays. Finally, in vivo experiments validated the role of the PTTG3P-miR-142-5p-IGF2BP3 axis in tumorigenesis. RESULTS: PTTG3P was upregulated in HCC and associated with poor prognosis. PTTG3P was a molecular sponge for miR-142-5p, leading to IGF2BP3 derepression and modulation of ferroptosis proteins, NRF2, SLC7A11 and GPX4. PTTG3P overexpression in HepG2 cells increased ferroptosis resistance, while PTTG3P knockdown in Huh7 cells sensitized these cells to ferroptosis. Additionally, the PTTG3P/miR-142-5p/IGF2BP3 axis influenced tumor growth in a xenograft mouse model. CONCLUSION: The PTTG3P/miR-142-5p/IGF2BP3 axis is a master regulator of ferroptosis in HCC. PTTG3P is a competing endogenous RNA (ceRNA) which sustains IGF2BP3-mediated ferroptosis resistance. Targeting the axis sensitizes HCC to ferroptosis and is potentially a novel therapeutic target to combat treatment resistance.
Key Findings
- PTTG3P is upregulated in hepatocellular carcinoma (HCC) and correlates with poor prognosis.
- PTTG3P acts as a molecular sponge for miR-142-5p, leading to derepression of IGF2BP3 and modulation of ferroptosis-related proteins NRF2, SLC7A11, and GPX4.
- Overexpression of PTTG3P increases ferroptosis resistance in HCC cells, while knockdown sensitizes cells to ferroptosis and reduces tumor growth in vivo.
Clinical Significance
Targeting the PTTG3P/miR-142-5p/IGF2BP3 axis may overcome ferroptosis resistance in HCC, offering a novel therapeutic strategy to improve treatment outcomes in this aggressive cancer.
Citation
Zhang Wenjuan, Liu Hao, Zhang Shuhanet al.. PTTG3P-miR-142-5p-IGF2BP3 axis governs ferroptosis in hepatocellular carcinoma. Discover oncology. 2026-Mar-22.