Abstract
Purpose
Melanoma is a malignant skin tumor caused by melanocytes and associated with high mortality rates. This study aims to investigate the specific mechanism of ZWZ-3 in melanoma proliferation and metastasis.
Methods
RNA sequencing was performed to identify the effect of ZWZ-3 on gene expression. siRNA was used to inhibit BIRC5 gene expression in the B16F10 cell line. A zebrafish tumor model was used to assess the therapeutic effect of ZWZ-3 in vivo. Mechanistic insights into the inhibition of tumor metastasis by ZWZ-3 were obtained through analysis of tumor tissue sections in mice.
Results
Our findings demonstrated that ZWZ-3 suppressed melanoma cell proliferation and migration. We performed RNA sequencing in melanoma cells after the treatment with ZWZ-3 and found that Birc5, which is closely associated with tumor metastasis, was significantly down-regulated. Bioinformatics analysis and the immuno-histochemical results of tissue chips for melanoma further confirmed the high expression of BIRC5 in melanoma and its effect on disease progression. Moreover, Birc5 knock-down significantly inhibited melanoma cell proliferation and metastasis, which was correlated with the β-catenin/HIF-1α/VEGF/MMPs pathway. Additionally, ZWZ-3 significantly inhibited tumor growth in the zebrafish tumor model without any evident side effects. Histological and immuno-histochemical analyses revealed that ZWZ-3 inhibited tumor cell metastasis by down-regulating HIF-1α, VEGF, and MMP9.
Conclusion
Our findings revealed that ZWZ-3 could downregulate BIRC5 and inhibit melanoma proliferation and metastasis through the β-catenin/HIF-1α/VEGF/MMPs pathway. Therefore, BIRC5 represents a promising therapeutic target for the treatment of melanoma.
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Data availability
The data sets generated during the current study are available from the corresponding author on reasonable requests.
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Acknowledgements
We thank Bullet Edits Limited for the linguistic editing and proofreading of the manuscript. This work was financially supported by the National Natural Science Foundation of China (82003716), Sichuan Science and Technology Program (2022YFS0631), Luzhou Science and Technology Projects (2022‐JYJ‐141), Southwest Medical University School‐level Project Fund (2022QN044).
Funding
This work was financially supported by the National Natural Science Foundation of China (82003716), Sichuan Science and Technology Program (2022YFS0631), Luzhou Science and Technology Projects (2022‐JYJ‐141), Southwest Medical University School‐level Project Fund (2022QN044).
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QH and LL designed the experiments and wrote the manuscript. YH and JX analyzed the data. QH, JW and TX performed the experiments. CL and XX conceived and supervised the project. All authors read and approved the final manuscript.
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He, Q., He, Y., Li, C. et al. Downregulated BIRC5 inhibits proliferation and metastasis of melanoma through the β-catenin/HIF-1α/VEGF/MMPs pathway. J Cancer Res Clin Oncol 149, 16797–16809 (2023). https://doi.org/10.1007/s00432-023-05425-3
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DOI: https://doi.org/10.1007/s00432-023-05425-3