Abstract
Metastatic melanoma remains a challenging disease. Understanding the molecular mechanisms how melanoma becomes metastatic is therefore of interest. Herein we show that downregulation of the AP-1 transcription factor member Fra-2 in melanoma cells is associated with an aggressive melanoma phenotype in vitro and in vivo. In vitro, Fra-2 knockdown in melanoma cells promoted cell migration and invasion associated with increased Snail-1, Twist-1/2, and matrix metalloproteinase-2 (MMP-2) expression. In vivo, Fra-2 knockdown in a melanoma cell line led to increased metastasis into the lungs and liver. The increased metastatic potential of Fra-2 knockdown melanoma cells was likely due to an accelerated cell cycle transition and increased tissue angiogenesis. Using Fra-2 knockdown cell lines microarray analysis, we identified the protein Fam212b (family with sequence similarity 212 member B) as a downstream target of Fra-2. By additional knockdown of Fam212b in Fra-2 mutant cells, we mitigated the cell migration, invasion, and cell cycle transition phenotype induced by Fra-2 knockdown. Furthermore, Fam212b overexpression enhanced β-catenin pathway. Finally, Fam212b expression is correlated with increased melanoma metastasis and poor clinical outcomes in human patients. In summary, these findings reveal the Fra-2-Fam212b axis as a new pathway of melanoma metastasis, which can be in the future used as potential marker of the metastatic properties of melanoma.
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Acknowledgements
We thank technicians from Shanghai Zuo Cheng Bio Co., Ltd. for providing excellent support for the immunohistochemistry experiments. This study was supported by grants from the Shanghai Science and Technology Committee, Shanghai International Communication Key Project (14430712000, 14430712001, and 14430712002), the National Natural Science Foundation of China (Nos. 81771729, Nos. 81802362, Nos. 81801593), and the Deutsche Forschungs-gemeinschaft (IZKF projekt D23, A01-CRC1181, microBone-SPP1468; BO3811/1-5, BO3811/1-6, BO3811/1-7, and Emmy Noether).
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Chen, GL., Li, R., Chen, XX. et al. Fra-2/AP-1 regulates melanoma cell metastasis by downregulating Fam212b. Cell Death Differ 28, 1364–1378 (2021). https://doi.org/10.1038/s41418-020-00660-4
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DOI: https://doi.org/10.1038/s41418-020-00660-4
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