ATF-3 expression inhibits melanoma growth by downregulating ERK and AKT pathways.
ATF-3 expression inhibits melanoma growth by downregulating ERK and AKT pathways.
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ATF-3 表达通过下调 ERK 和 AKT 途径抑制黑色素瘤生长。
DOI：
10.1038/s41374-020-00516-y
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Murphy GF
中科院分区：
文献类型：
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作者：
Zu T;Wang D;Xu S;Lee CAA;Zhen E;Yoon CH;Abarzua P;Wang S;Frank NY;Wu X;Lian CG;Murphy GF
激活转录因子 3 (ATF-3) 是一种环 AMP 依赖性转录因子，已被证明在黑色素瘤中发挥调节作用，但其在肿瘤进展过程中的功能仍不清楚。在这里，我们证明 ATF-3 在黑色素瘤中表现出肿瘤抑制功能。具体来说，随着黑色素瘤从痣发展到原发性黑色素瘤再到转移性患者黑色素瘤，ATF-3核表达显着减少，低表达与不良预后相关。在培养的人转移性黑色素瘤细胞系中也发现 ATF-3 的表达显着降低。重要的是，在体外，转移性黑色素瘤细胞系中 ATF-3 的过度表达显着抑制细胞生长、迁移和侵袭。以及消除体内人类黑色素瘤异种移植小鼠模型中的肿瘤生长。 RNA-seq 分析揭示了 ATF-3 过表达的黑色素瘤细胞系中 ERK 和 AKT 通路的下调以及细胞凋亡相关基因的上调，这一点通过蛋白质印迹分析得到了进一步验证。总之，这项研究证明 ATF-3 表达减少与黑色素瘤毒力相关，因此为新疗法和预后生物标志物应用提供了潜在靶点。
Activating transcription factor 3 (ATF-3), a cyclic AMP-dependent transcription factor, has been shown to play a regulatory role in melanoma, although its function during tumor progression remains unclear. Here, we demonstrate that ATF-3 exhibits tumor suppressive function in melanoma. Specifically, ATF-3 nuclear expression was significantly diminished with melanoma progression from nevi to primary to metastatic patient melanomas, correlating low expression with poor prognosis. Significantly low expression of ATF-3 was also found in cultured human metastatic melanoma cells lines. Importantly, overexpression of ATF-3 in metastatic melanoma cell lines significantly inhibited cell growth, migration, and invasion in vitro; as well as abrogated tumor growth in human melanoma xenograft mouse model in vivo. RNA-seq analysis revealed downregulation of ERK and AKT pathways and upregulation in apoptotic-related genes in ATF-3 overexpressed melanoma cell lines, which was further validated by Western-blot analysis. In summary, this study demonstrated that diminished ATF-3 expression is associated with melanoma virulence and thus provides a potential target for novel therapies and prognostic biomarker applications.