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Action of HMGB1 on miR-221/222 cluster in neuroblastoma cell lines
Emanuela Mari1, Alessandra Zicari1, Flavia Fico1
1Department of Experimental Medicine, Sapienza University of Rome, I-00161 Rome, Italy.
Abstract:
microRNA (miR/miRNA) are small non-coding RNAs that control gene expression at the post-transcriptional level by targeting mRNAs. Aberrant expression of miRNAs is often observed in different types of cancer. Specific miRNAs function as tumor suppressors or oncogenes and interfere with various aspects of carcinogenesis, including differentiation, proliferation and invasion. Upregulation of miRNAs 221 and 222 has been shown to induce a malignant phenotype in numerous human cancers via inhibition of phosphatase and tensin homolog (PTEN) expression. Neuroblastoma is the most common extracranial solid malignancy in children, which is characterized by cellular heterogeneity that corresponds to different clinical outcomes. The different cellular phenotypes are associated with different gene mutations and miRs that control genetic and epigenetic factors. For this reason miRs are considered a potential therapeutic target in neuroblastoma. The aim of the present study was to investigate the mechanisms by which extracellular high mobility group box 1 (HMGB1) promotes cell growth in neuroblastoma. SK-N-BE(2) and SH-SY5Y neuroblastoma derived cell lines were transfected with the antisense oligonucleotides, anti-miR-221 and -222, followed by treatment with HMGB1 to investigate the expression of the oncosuppressor PTEN. In this study, it was demonstrated that HMGB1, which is released by damaged cells and tumor cells, upregulates miR-221/222 oncogenic clusters in the two human neuroblastoma derived cell lines. The results revealed that the oncogenic cluster miRs 221/222 were more highly expressed by the most undifferentiated cell line [SK-N-BE(2)] compared with the the less tumorigenic cell line (SH-SY5Y) and that exogenous HMGB1 increases this expression. In addition, HMGB1 modulates PTEN expression via miR-221/222, as demonstrated by transiently blocking miR-221/222 with anti-sense oligonucleotides. These results may lead to the development of novel therapeutic strategies for neuroblastoma.
Insights
Extracellular high mobility group box 1 (HMGB1) upregulates oncogenic microRNAs 221/222 in neuroblastoma cells. This HMGB1-mediated pathway inhibits tumor suppressor PTEN, promoting cancer growth and suggesting new therapeutic targets.
Area of Science:
- Molecular Biology
- Oncology
- Gene Regulation
Background:
- MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression, often dysregulated in cancer.
- Specific miRNAs, like miR-221 and miR-222, act as oncogenes by suppressing tumor suppressors such as PTEN.
- Neuroblastoma, a pediatric cancer, exhibits cellular heterogeneity linked to distinct genetic and epigenetic profiles, making miRNAs potential therapeutic targets.
Purpose of the Study:
- To investigate the role of extracellular high mobility group box 1 (HMGB1) in promoting neuroblastoma cell growth.
- To elucidate the mechanism by which HMGB1 influences the expression of miR-221/222 and phosphatase and tensin homolog (PTEN) in neuroblastoma cell lines.
Main Methods:
- Utilized neuroblastoma cell lines (SK-N-BE(2) and SH-SY5Y).
- Employed antisense oligonucleotides (anti-miR-221 and anti-miR-222) to block specific miRNA activity.
- Treated cells with HMGB1 and analyzed PTEN expression levels.
Main Results:
- Extracellular HMGB1 was found to upregulate the oncogenic miR-221/222 cluster in both neuroblastoma cell lines.
- Higher expression of miR-221/222 was observed in the more undifferentiated SK-N-BE(2) cells compared to SH-SY5Y cells.
- HMGB1 was demonstrated to modulate PTEN expression through the miR-221/222 pathway, as evidenced by miRNA inhibition.
Conclusions:
- HMGB1 promotes neuroblastoma cell growth by upregulating miR-221/222, leading to the inhibition of the tumor suppressor PTEN.
- The findings highlight a novel mechanism involving HMGB1, miR-221/222, and PTEN in neuroblastoma pathogenesis.
- This study provides a basis for developing novel therapeutic strategies targeting this pathway for neuroblastoma treatment.
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