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Long non-coding RNA STMN1P2 promotes breast cancer doxorubicin resistance by inhibiting pyroptosis through the
You-Ping Jin1, Bu-Jie Xu1, Xiu-Fen Zhang1
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
Abstract:
Chemotherapeutic resistance is a significant issue in the treatment of breast cancer, which is related to pyroptosis inhibition. Increasing evidence suggests that long non-coding RNAs (lncRNAs) contribute to tumorigenesis and drug resistance. In this study we investigated the role of the lncRNA STMN1P2 in doxorubicin resistance in breast cancer, as well as its correlation with pyroptosis inhibition. Our results showed that the expression levels of lncRNA STMN1P2 were significantly elevated in doxorubicin-resistant breast cancer tissues and cells. We demonstrated that knockdown of STMN1P2 reduced doxorubicin resistance in breast cancer cells; overexpression of STMN1P2 inhibited doxorubicin-induced pyroptosis by reducing the expression of NLRP3, ASC, caspase-1 and GSDMD. Furthermore, STMN1P2 directly bound to and positively regulated heterogeneous nuclear ribonucleoprotein U (hnRNPU), and knockdown of hnRNPU reversed the inhibitory effect of STMN1P2 on pyroptosis and its ability to promote chemoresistance. In doxorubicin-resistant cells, hnRNPU directly bound to enhancer of zeste homologue 2 (EZH2), and STMN1P2 enhanced hnRNPU recruitment of EZH2 and increased EZH2 protein stability. EZH2 acted as a transcription factor to inactivate TNF receptor-associated factor 6 (TRAF6), thereby repressing the binding of TRAF6 with MALT1 and caspase-1, attenuating the canonical pathways of pyroptosis. In MCF7/DOX cells xenograft nude mouse model, we demonstrated that knockdown of STMN1P2 significantly enhanced the suppression of doxorubicin on the tumour growth. This study provides new clues and approaches for the prevention and treatment of breast cancer chemoresistance.
Insights
This study reveals that the long non-coding RNA STMN1P2 promotes chemoresistance in breast cancer by inhibiting pyroptosis. Reducing STMN1P2 levels can re-sensitize cancer cells to doxorubicin, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chemotherapeutic resistance, particularly to doxorubicin, is a major challenge in breast cancer treatment.
- Pyroptosis inhibition is linked to chemoresistance, and long non-coding RNAs (lncRNAs) are implicated in cancer progression and drug resistance.
Purpose of the Study:
- To investigate the role of the lncRNA STMN1P2 in doxorubicin resistance in breast cancer.
- To explore the correlation between STMN1P2 and pyroptosis inhibition in breast cancer cells.
Main Methods:
- Quantitative real-time PCR to measure STMN1P2 expression in resistant vs. sensitive tissues and cells.
- Cell viability assays and pyroptosis marker analysis (NLRP3, ASC, caspase-1, GSDMD) after STMN1P2 knockdown or overexpression.
- RNA immunoprecipitation and Western blotting to assess interactions between STMN1P2, hnRNPU, EZH2, TRAF6, MALT1, and caspase-1.
- Xenograft mouse models to evaluate the in vivo effect of STMN1P2 knockdown on tumor growth suppression by doxorubicin.
Main Results:
- STMN1P2 expression was significantly higher in doxorubicin-resistant breast cancer tissues and cells.
- Knockdown of STMN1P2 decreased doxorubicin resistance and restored pyroptosis.
- STMN1P2 positively regulated hnRNPU, which in turn recruited EZH2 to suppress pyroptosis pathways (TRAF6-MALT1-caspase-1).
- Knockdown of STMN1P2 in vivo significantly enhanced doxorubicin's tumor growth suppression.
Conclusions:
- STMN1P2 plays a critical role in promoting doxorubicin resistance in breast cancer by inhibiting pyroptosis through the hnRNPU/EZH2/TRAF6 pathway.
- Targeting STMN1P2 presents a promising strategy for overcoming breast cancer chemoresistance.
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