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Metformin inhibits melanoma cell metastasis by suppressing the miR-5100/SPINK5/STAT3 axis
Dong Suwei1,2, Xiao Yanbin3,4, Wang Jianqiang1
1Department of Orthopaedics, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, People's Republic of China.
Abstract:
Melanoma is the most lethal skin cancer characterized by its high metastatic potential. It is urgent to find novel therapy strategies to overcome this feature. Metformin has been confirmed to suppress invasion and migration of various types of cancer. However, additional mechanisms underlying the antimetastatic effect of metformin on melanoma require further investigation. Here, we performed microarray analysis and uncovered an altered mRNA and miRNA expression profile between melanoma and nevus. Luciferase reporter assay confirmed that miR-5100 targets SPINK5 to activate STAT3 phosphorylation. Migration and wound healing assays showed that the miR-5100/SPINK5/STAT3 axis promotes melanoma cell metastasis; the mechanism was proven by initiation of epithelial-mesenchymal transition. Co-immunoprecipitation (Co-IP) further confirmed an indirect interaction between SPINK5 and STAT3. Furthermore, metformin dramatically inhibited miR-5100/SPINK5/STAT3 pathway, and decreased B16-F10 cell metastasis to lung in C57 mouse module. Intriguingly, pretreatment of metformin before melanoma cell injection improved this effect further. These findings exposed the underlying mechanisms of action of metformin and update the use of this drug to prevent metastasis in melanoma.
Insights
Metformin inhibits melanoma metastasis by targeting the miR-5100/SPINK5/STAT3 pathway. This study reveals metformin
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background:
- Melanoma, a lethal skin cancer, exhibits high metastatic potential, necessitating novel therapeutic strategies.
- Metformin is known to suppress cancer invasion and migration, but its antimetastatic mechanisms in melanoma require further elucidation.
Discussion:
- Microarray analysis revealed distinct mRNA and miRNA profiles between melanoma and nevus.
- The miR-5100/SPINK5/STAT3 axis was identified as a key promoter of melanoma cell metastasis via epithelial-mesenchymal transition.
- Metformin was shown to significantly inhibit this pathway and reduce lung metastasis in a mouse model.
Key Insights:
- Luciferase assays confirmed miR-5100 targets SPINK5, activating STAT3 phosphorylation.
- Co-immunoprecipitation demonstrated an indirect interaction between SPINK5 and STAT3.
- Metformin effectively suppressed melanoma cell metastasis by inhibiting the miR-5100/SPINK5/STAT3 pathway.
Outlook:
- Findings elucidate metformin's antimetastatic mechanisms in melanoma.
- Metformin's potential use in preventing melanoma metastasis warrants further clinical investigation.
- This research provides a basis for repurposing metformin as an adjuvant therapy for melanoma.
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