除了紫外线 (UV) 辐射 (UVR) 之外，黑色素瘤发展中与 BRAFV600E 癌基因一起发挥作用的机制也引起了人们的极大兴趣。对人类黑色素瘤肿瘤的分析[数据来自癌症基因组图谱 (TCGA)] 显示，50% 或更多的样本不表达或表达少量丝氨酸/苏氨酸蛋白激酶 STK11（也称为 LKB1）蛋白。在这里，我们报告说，在小鼠模型中，伴随的新生儿 BrafV600E 激活和黑素细胞中 Lkb1 肿瘤抑制因子的消融导致了黑色素瘤的完全发展。与 BrafV600E 照射的小鼠相比，出生后单次 UVB 辐射对 Lkb1 耗尽的小鼠黑色素瘤的发病没有影响，但增加了肿瘤的多样性。与这些发现和之前的报告一致，Lkb1 缺失的辐射小鼠表现出 DNA 损伤修复 (DDR) 缺陷。组织学上，缺乏 Lkb1 的肿瘤在神经样肿瘤形态上丰富。肿瘤样本突变基因的遗传图谱和基因集富集分析表明，Lkb1 的缺失促进了与神经分化过程相关的改变基因的选择。因此，这些结果表明 Lkb1 的缺失与 BrafV600E 和 UVR 协同作用，损害 DDR 并增加黑色素瘤的多样性和神经样去分化。© 2024 作者。约翰·威利出版的《分子肿瘤学》

The mechanisms that work alongside BRAFV600E oncogene in melanoma development, in addition to ultraviolet (UV) radiation (UVR), are of great interest. Analysis of human melanoma tumors [data from The Cancer Genome Atlas (TCGA)] revealed that 50% or more of the samples expressed no or low amounts of serine/threonine protein kinase STK11 (also known as LKB1) protein. Here, we report that, in a mouse model, concomitant neonatal BrafV600E activation and Lkb1 tumor suppressor ablation in melanocytes led to full melanoma development. A single postnatal dose of UVB radiation had no effect on melanoma onset in Lkb1-depleted mice compared with BrafV600E-irradiated mice, but increased tumor multiplicity. In concordance with these findings and previous reports, Lkb1-null irradiated mice exhibited deficient DNA damage repair (DDR). Histologically, tumors lacking Lkb1 were enriched in neural-like tumor morphology. Genetic profiling and gene set enrichment analyses of tumor sample mutated genes indicated that loss of Lkb1 promoted the selection of altered genes associated with neural differentiation processes. Thus, these results suggest that the loss of Lkb1 cooperates with BrafV600E and UVR, impairing the DDR and increasing melanoma multiplicity and neural-like dedifferentiation.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.