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.

转移性黑色素瘤仍然是一种具有挑战性的疾病。因此，了解黑色素瘤如何转移的分子机制是有意义的。在这里，我们显示黑色素瘤细胞中 AP-1 转录因子成员 Fra-2 的下调与体外和体内侵袭性黑色素瘤表型有关。在体外，黑色素瘤细胞中的 Fra-2 敲低促进了与增加的 Snail-1、Twist-1/2 和基质金属蛋白酶 2 (MMP-2) 表达相关的细胞迁移和侵袭。在体内，黑色素瘤细胞系中的 Fra-2 敲低导致向肺和肝脏的转移增加。Fra-2 敲低黑色素瘤细胞的转移潜能增加可能是由于细胞周期转换加速和组织血管生成增加。使用 Fra-2 敲低细胞系微阵列分析，我们将蛋白质 Fam212b（具有序列相似性 212 成员 B 的家族）鉴定为 Fra-2 的下游靶标。通过在 Fra-2 突变细胞中额外敲低 Fam212b，我们减轻了由 Fra-2 敲低诱导的细胞迁移、侵袭和细胞周期转换表型。此外，Fam212b 过表达增强了 β-连环蛋白途径。最后，Fam212b 表达与人类患者黑色素瘤转移增加和临床结果不佳相关。总之，这些发现揭示了 Fra-2-Fam212b 轴是黑色素瘤转移的新途径，未来可用作黑色素瘤转移特性的潜在标志物。和由 Fra-2 敲低诱导的细胞周期转换表型。此外，Fam212b 过表达增强了 β-连环蛋白途径。最后，Fam212b 表达与人类患者黑色素瘤转移增加和临床结果不佳相关。总之，这些发现揭示了 Fra-2-Fam212b 轴是黑色素瘤转移的新途径，未来可用作黑色素瘤转移特性的潜在标志物。和由 Fra-2 敲低诱导的细胞周期转换表型。此外，Fam212b 过表达增强了 β-连环蛋白途径。最后，Fam212b 表达与人类患者黑色素瘤转移增加和临床结果不佳相关。总之，这些发现揭示了 Fra-2-Fam212b 轴是黑色素瘤转移的新途径，未来可用作黑色素瘤转移特性的潜在标志物。