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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
MiR-4458/human antigen R (HuR) modulates PBX3 mRNA stability in melanoma tumorigenesis
Henghua Zhou1, Yamin Rao1, Qilin Sun2
1Department of Pathology, Shanghai Ninth People's Hospital, Affiliated to Shanghai Jiaotong University School of Medicine, Center for Specialty Strategy Research of Shanghai JiaoTong University China Hospital Development Institute, Shanghai, 200011, China.
Abstract:
Melanoma, a malignancy of the melanocyte, is characterized as the most fatal skin cancer with an increasing incidence. Of note, in spite of great attempts made for better treatment, the therapeutic outcome is barely satisfactory. Abnormal expression of microRNAs (miRNAs) acting as oncogenes or tumor suppressor genes, is frequently implicated in multiple human cancers, including melanoma. Here, we found that miRNA-4458, a reportedly tumor-suppressive miRNA in several cancers, was downregulated in melanoma cells. Besides, our findings indicated that microRNA-4458 (miR-4458) hindered cell proliferation and migration, yet induced apoptosis in melanoma. Mechanical interaction of miR-4458 and PBX3 mRNA, thereby inhibiting PBX3 expression in melanoma cells, was also presented in this work. Human antigen R (HuR) was reported to be greatly upregulated in diverse cancers and HuR-dependent stabilization of target gene contributed a lot to tumor progression. In this study, it revealed the stabilization of PBX3 mRNA by HuR, thereby boosting PBX3 expression. Lastly, we concluded that miR-4458 and HuR modulated the expression of PBX3 in a competitive manner in melanoma tumorigenesis, which might yield a novel insight into the molecular pathogenesis of melanoma.
Insights
MicroRNA-4458 (miR-4458) is downregulated in melanoma, inhibiting cancer cell growth and migration. It competitively regulates PBX3 expression with HuR, offering new insights into melanoma pathogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Gene Regulation
Background:
- Melanoma is an aggressive skin cancer with poor therapeutic outcomes.
- MicroRNAs (miRNAs) are implicated in cancer, acting as oncogenes or tumor suppressors.
- Abnormal miRNA expression is common in various human cancers, including melanoma.
Purpose of the Study:
- To investigate the role of microRNA-4458 (miR-4458) in melanoma.
- To elucidate the molecular mechanisms underlying miR-4458's function in melanoma cells.
- To explore the interaction between miR-4458, PBX3, and HuR in melanoma tumorigenesis.
Main Methods:
- Quantitative real-time PCR to measure miR-4458 and PBX3 expression.
- Cell proliferation, migration, and apoptosis assays.
- Western blotting to assess protein levels.
- Luciferase reporter assays to confirm target interaction.
Main Results:
- miR-4458 was significantly downregulated in melanoma cells.
- Overexpression of miR-4458 suppressed melanoma cell proliferation and migration while inducing apoptosis.
- miR-4458 directly targeted PBX3 mRNA, inhibiting PBX3 expression.
- HuR stabilized PBX3 mRNA, increasing PBX3 expression.
- miR-4458 and HuR competitively regulated PBX3 expression in melanoma.
Conclusions:
- miR-4458 acts as a tumor suppressor in melanoma by inhibiting cell proliferation and migration and inducing apoptosis.
- The miR-4458/PBX3/HuR axis represents a novel regulatory pathway in melanoma pathogenesis.
- Targeting this pathway may offer new therapeutic strategies for melanoma treatment.
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