Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
Mol Cancer Res. 2013 Oct;11(10):1166-78. doi: 10.1158/1541-7786.MCR-13-0006. Epub 2013 Jul 12.
Melanoma genomes contain thousands of alterations including: mutations, copy number alterations, structural aberrations, and methylation changes. The bulk of this variation is stochastic and functionally neutral, with only a small minority representing "drivers" that contribute to the genesis and maintenance of tumors. Drivers are often directly or inversely correlated across tumors, reflecting the molecular and regulatory signaling pathways in which they operate. Here, a profile of genetic and epigenetic drivers in 110 human melanoma cell lines was generated and searched for non-random distribution patterns. Statistically significant mutual exclusivity was revealed among components of each of the p16(INK4A)-CDK4-RB, RAS-RAF-MEK-ERK and PI3K-AKT signaling pathways. In addition, an inverse correlation was observed between promoter hypermethylation of retinoic acid receptor β (RARB) and CDKN2A alterations affecting p14(ARF) (P < 0.0001), suggesting a functional link between RARβ signaling and the melanoma-suppressive activities of p14(ARF). Mechanistically, all-trans retinoic acid (ATRA) treatment increased the expression of p14(ARF) in primary human melanocytes and the steady-state levels of p14(ARF) in these cells were shown to be regulated via RARβ. Furthermore, the ability of ATRA to induce senescence is reduced in p14(ARF)-depleted melanocytes, and we provide proof-of-concept that ATRA can induce irreversible growth arrest in melanoma cells with an intact RARβ-p14(ARF) signaling axis, independent of p16(INK4A) and p53 status.
These data highlight the power of mutual exclusivity analysis of cancer drivers to unravel molecular pathways and establish a previously unrecognized cross-talk between RARβ and p14(ARF) with potential implications for melanoma treatment.
黑色素瘤基因组包含数千种改变，包括：突变、拷贝数改变、结构异常和甲基化改变。这种变异的大部分是随机的和功能上的中性的，只有一小部分代表“驱动因素”，它们有助于肿瘤的发生和维持。驱动因素通常在肿瘤之间直接或间接相关，反映了它们作用的分子和调节信号通路。在这里，生成了 110 个人类黑色素瘤细胞系的遗传和表观遗传驱动因素图谱，并搜索了非随机分布模式。p16(INK4A)-CDK4-RB、RAS-RAF-MEK-ERK 和 PI3K-AKT 信号通路的每个组成部分之间都显示出统计学上显著的互斥性。此外，还观察到维甲酸受体 β (RARB) 启动子超甲基化与影响 p14(ARF) 的 CDKN2A 改变之间存在反向相关性(P < 0.0001)，表明 RARβ 信号与黑色素瘤抑制活性之间存在功能联系p14(ARF)。从机制上讲，全反式维甲酸(ATRA)处理增加了原代人黑素细胞中 p14(ARF)的表达，并且这些细胞中 p14(ARF)的稳定水平被证明是通过 RARβ 调节的。此外，在 p14(ARF)耗尽的黑素细胞中，ATRA 诱导衰老的能力降低，并且我们提供了概念验证，表明 ATRA 可以在具有完整 RARβ-p14(ARF)信号轴的黑色素瘤细胞中诱导不可逆的生长停滞，独立于 p16(INK4A)和 p53 状态。
这些数据突出了相互排斥性分析癌症驱动因素的力量，以揭示分子途径，并建立 RARβ 和 p14(ARF) 之间以前未被认识到的交叉对话，这可能对黑色素瘤治疗有影响。
