PDF(Pubmed)
Abstract：
BRAFV600E mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAFV600E drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a \'just-right\' level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in BRAFV600E-mutant adenomas/polyps in mice and patients. In Vil1-Cre;BRAFLSL-V600E/+;Ptk2fl/fl mice, Fak deletion maximized BRAFV600E\'s oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAFV600E-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation increased the level of Lgr4, promoting intestinal stemness and cecal tumor formation. Our findings show that a \'just-right\' ERK signaling optimal for BRAFV600E-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.
摘要：
BRAFV600E突变是结直肠癌锯齿状途径中的驱动突变。BRAFV600E通过组成型下游细胞外信号调节激酶（ERK）激活驱动肿瘤发生，但高强度ERK激活也可引发肿瘤抑制。是否以及如何将致癌ERK信号传导内在地调整到肿瘤发生的最佳水平尚不确定。在这项研究中,我们发现,在小鼠和患者的BRAFV600E突变型腺瘤/息肉中,FAK(粘着斑激酶)表达降低.在Vil1-Cre;BRAFLSL-V600E/+;Ptk2fl/fl小鼠,Fak缺失使BRAFV600E的致癌活性最大化，盲肠肿瘤发病率增加至100%。机械上,我们的结果表明，Fak损失，在不危害BRAFV600E诱导的ERK通路转录输出的情况下，降低EGFR（表皮生长因子受体）依赖性ERK磷酸化。ERK磷酸化的减少增加了Lgr4的水平，促进了肠干性和盲肠肿瘤的形成。我们的发现表明，通过Fak丢失介导的ERK磷酸化下调，可以实现BRAFV600E诱导的盲肠肿瘤形成的最佳ERK信号传导。
