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Published on: December 1, 2023
Long Noncoding RNA MPRL Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via Disruption of Pre-miRNA
Tian Tian1, Xiaobin Lv2,3, Guokai Pan1,4
1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Guangzhou, China.
Purpose:
The overall biological roles and clinical significance of most long noncoding RNAs (lncRNA) in chemosensitivity are not fully understood. We investigated the biological function, mechanism, and clinical significance of lncRNA NR_034085, which we termed miRNA processing-related lncRNA (MPRL), in tongue squamous cell carcinoma (TSCC).
Experimental Design:
LncRNA expression in TSCC cell lines with cisplatin treatment was measured by lncRNA microarray and confirmed in TSCC tissues. The functional roles of MPRL were demonstrated by a series of in vitro and in vivo experiments. The miRNA profiles, RNA pull-down, RNA immunoprecipitation, serial deletion analysis, and luciferase analyses were used to investigate the potential mechanisms of MPRL.
Results:
We found that MPRL expression was significantly upregulated in TSCC cell lines treated with cisplatin and transactivated by E2F1. MPRL controlled mitochondrial fission and cisplatin sensitivity through miR-483-5p. In exploring the underlying interaction between MPRL and miR-483-5p, we identified that cytoplasmic MPRL directly binds to pre-miR-483 within the loop region and blocks pre-miR-483 recognition and cleavage by TRBP-DICER-complex, thereby inhibiting miR-483-5p generation and upregulating miR-483-5p downstream target-FIS1 expression. Furthermore, overexpression or knockdown MPRL altered tumor apoptosis and growth in mouse xenografts. Importantly, we found that high expression of MPRL and pre-miR-483, and low expression of miR-483-5p were significantly associated with neoadjuvant chemosensitivity and better TSCC patients' prognosis.
Conclusions:
We propose a model in which lncRNAs impair microprocessor recognition and are efficient of pre-miRNA cropping. In addition, our study reveals a novel regulatory network for mitochondrial fission and chemosensitivity and new biomarkers for prediction of neoadjuvant chemosensitivity in TSCC.These findings uncover a novel mechanism by which lncRNA determines mitochondrial fission and cisplatin chemosensitivity by inhibition of pre-miRNA processing and provide for the first time the rationale for lncRNA and miRNA biogenesis for predicting chemosensitivity and patient clinical prognosis.
Insights
This study reveals that the long noncoding RNA MPRL (miRNA processing-related lncRNA) regulates cisplatin sensitivity in tongue squamous cell carcinoma by inhibiting miRNA processing. High MPRL expression predicts better chemosensitivity and prognosis in TSCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The roles of long noncoding RNAs (lncRNAs) in cancer chemosensitivity remain largely undefined.
- Understanding lncRNA mechanisms is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To investigate the function, mechanism, and clinical significance of lncRNA NR_034085 (MPRL) in tongue squamous cell carcinoma (TSCC) chemosensitivity.
- To elucidate MPRL's role in cisplatin resistance and patient prognosis.
Main Methods:
- lncRNA microarray analysis in cisplatin-treated TSCC cell lines and tissues.
- In vitro and in vivo experiments to determine MPRL's functional roles.
- miRNA profiling, RNA pull-down, RNA immunoprecipitation, and luciferase assays to investigate MPRL's mechanism.
Main Results:
- MPRL expression was upregulated in TSCC cells upon cisplatin treatment and transactivated by E2F1.
- MPRL inhibits miR-483-5p biogenesis by directly binding to pre-miR-483, thus controlling mitochondrial fission and cisplatin sensitivity.
- High MPRL and pre-miR-483, and low miR-483-5p expression correlated with neoadjuvant chemosensitivity and improved TSCC patient prognosis.
Conclusions:
- MPRL acts as a regulator of mitochondrial fission and cisplatin chemosensitivity by inhibiting pre-miRNA processing.
- MPRL, pre-miR-483, and miR-483-5p serve as novel biomarkers for predicting neoadjuvant chemosensitivity and clinical outcomes in TSCC.
- This study establishes a novel lncRNA-miRNA regulatory network impacting chemosensitivity and patient prognosis in TSCC.
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