Claps Giuseppina, Cheli Yann, Zhang Tongwu, Scortegagna Marzia, Lau Eric, Kim Hyungsoo, Qi Jianfei, Li Jian-Liang, James Brian, Dzung Andreas, Levesque Mitchell P, Dummer Reinhard, Hayward Nicholas K, Bosenberg Marcus, Brown Kevin M, Ronai Ze'ev A
Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Division of Cancer Epidemiology and Genetics, Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD 20892, USA.
Cell Rep. 2016 May 31;15(9):1884-92. doi: 10.1016/j.celrep.2016.04.072. Epub 2016 May 19.
Melanoma is one of the most lethal cutaneous malignancies, characterized by chemoresistance and a striking propensity to metastasize. The transcription factor ATF2 elicits oncogenic activities in melanoma, and its inhibition attenuates melanoma development. Here, we show that expression of a transcriptionally inactive form of Atf2 (Atf2(Δ8,9)) promotes development of melanoma in mouse models. Atf2(Δ8,9)-driven tumors show enhanced pigmentation, immune infiltration, and metastatic propensity. Similar to mouse Atf2(Δ8,9), we have identified a transcriptionally inactive human ATF2 splice variant 5 (ATF2(SV5)) that enhances the growth and migration capacity of cultured melanoma cells and immortalized melanocytes. ATF2(SV5) expression is elevated in human melanoma specimens and is associated with poor prognosis. These findings point to an oncogenic function for ATF2 in melanoma development that appears to be independent of its transcriptional activity.
黑色素瘤是最致命的皮肤恶性肿瘤之一，其特征是具有化学抗性和显著的转移倾向。转录因子ATF2在黑色素瘤中引发致癌活性，对其抑制可减弱黑色素瘤的发展。在此，我们表明转录无活性形式的Atf2（Atf2(Δ8,9)）的表达促进小鼠模型中黑色素瘤的发展。Atf2(Δ8,9)驱动的肿瘤表现出增强的色素沉着、免疫浸润和转移倾向。与小鼠Atf2(Δ8,9)相似，我们鉴定出一种转录无活性的人类ATF2剪接变体5（ATF2(SV5)），它增强了培养的黑色素瘤细胞和永生化黑素细胞的生长和迁移能力。ATF2(SV5)在人类黑色素瘤标本中的表达升高，且与预后不良相关。这些发现表明ATF2在黑色素瘤发展中具有致癌功能，这似乎与其转录活性无关。
