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Genetic Profiling and Genome-Scale Dropout Screening to Identify Therapeutic Targets in Mouse Models of Malignant Peripheral Nerve Sheath Tumor
Published on: August 25, 2023
MicroRNA-21 correlates with tumorigenesis in malignant peripheral nerve sheath tumor (MPNST) via programmed cell
Satoru Itani1, Toshiyuki Kunisada, Yuki Morimoto
1Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Purpose:
We investigated the miRNA profile in peripheral nerve tumors and clarified the involvement of miRNA in the development and progression of MPNST in comparison with neurofibroma (NF). In addition, we attempted to seek associations between the miRNA and their potential targets in MPNST.
Methods:
Global miRNA expression profiling was investigated for clinical samples of 6 MPNSTs and 6 NFs. As detected by profiling analysis, the expressions of miR-21 in clinical samples of 12 MPNSTs, 11 NFs, and 5 normal nerves, and 3 MPNST cell lines were compared using quantitative real-time reverse transcription PCR. MPNST cell line (YST-1) was transfected with miR-21 inhibitor to study its effects on cell proliferation, caspase activity, and the expression of miR-21 targets.
Results:
Analysis of miRNA expression profiles in MPNST and NF revealed significantly altered expression levels of nine miRNAs, one of those, miR-21, and its putative target, programmed cell death protein 4 (PDCD4), were selected for further studies. miR-21 expression level in MPNST was significantly higher than that in NF (P < 0.05). In MPNST cells, transfection of miR-21 inhibitor significantly increased caspase activity (P < 0.01), significantly suppressed cell growth (P < 0.05), and upregulated protein level of PDCD4, indicating that miR-21 inhibitor could induce cell apoptosis of MPNST cells.
Conclusions:
These results suggest that miR-21 plays an important role in MPNST tumorigenesis and progression through its target, PDCD4. MiR-21 and PDCD4 may be candidate novel therapeutic targets against the development or progression of MPNSTs.
Insights
MicroRNA-21 (miR-21) is elevated in malignant peripheral nerve sheath tumors (MPNSTs) and drives tumor growth by suppressing PDCD4. Inhibiting miR-21 may offer a new therapeutic strategy for MPNST.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive cancers.
- Understanding the molecular mechanisms driving MPNST development is crucial for effective treatment.
- MicroRNAs (miRNAs) are key regulators of gene expression implicated in various cancers.
Purpose of the Study:
- To investigate miRNA profiles in MPNSTs compared to neurofibromas (NFs).
- To elucidate the role of specific miRNAs, particularly miR-21, in MPNST development and progression.
- To identify potential miRNA targets involved in MPNST pathogenesis.
Main Methods:
- Global miRNA expression profiling of clinical MPNST and NF samples.
- Quantitative real-time PCR to validate miR-21 expression in MPNSTs, NFs, and normal nerves.
- In vitro studies using MPNST cell lines to assess the impact of miR-21 inhibition on cell proliferation, apoptosis, and target gene expression.
Main Results:
- Nine miRNAs showed significantly altered expression between MPNSTs and NFs.
- miR-21 expression was significantly higher in MPNSTs compared to NFs.
- Inhibiting miR-21 in MPNST cells increased apoptosis, suppressed growth, and upregulated its target, PDCD4.
Conclusions:
- miR-21 plays a critical role in MPNST tumorigenesis and progression via its target PDCD4.
- miR-21 and PDCD4 represent potential therapeutic targets for MPNST treatment.
- Further research into miR-21 targeted therapies for MPNST is warranted.
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