Zhang Qiang, Zhang Yaqing, Parsels Joshua D, Lohse Ines, Lawrence Theodore S, Pasca di Magliano Marina, Sun Yi, Morgan Meredith A
Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Neoplasia. 2016 Nov;18(11):666-673. doi: 10.1016/j.neo.2016.08.009. Epub 2016 Oct 18.
Pancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation between Kras mutation and Fbxw7 inactivation in pancreatic tumorigenesis, we generated P48-Cre;LSL-Kras;Fbxw7 (KFC) compound mice. We found that KFC mice displayed accelerated tumorigenesis: all mice succumbed to pancreatic ductal adenocarcinoma (PDA) by 40 days of age, with PDA onset occurring by 2 weeks of age. PDA in KFC mice was preceded by earlier onset of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions, and associated with chromosomal instability and the accumulation of Fbxw7 substrates Yes-associated protein (Yap), c-Myc, and Notch. Using KFC and FBXW7-deficient human pancreatic cancer cells, we found that Yap silencing attenuated growth promotion by Fbxw7 deletion. Our data demonstrate that Fbxw7 is a potent suppressor of Kras-induced pancreatic tumorigenesis due, at least in part, to negative regulation of Yap.
由KRAS突变驱动的胰腺癌需要额外的突变才能实现肿瘤进展。肿瘤抑制因子FBXW7在胰腺癌中发生改变，但其对胰腺肿瘤发生的作用尚不清楚。为了确定Kras突变与Fbxw7失活在胰腺肿瘤发生中的潜在协同作用，我们构建了P48-Cre;LSL-Kras;Fbxw7（KFC）复合小鼠。我们发现KFC小鼠表现出加速的肿瘤发生：所有小鼠在40日龄时均死于胰腺导管腺癌（PDA），PDA在2周龄时开始出现。KFC小鼠的PDA之前出现更早的腺泡-导管化生（ADM）和胰腺上皮内瘤变（PanIN）病变，并与染色体不稳定性以及Fbxw7底物Yes相关蛋白（Yap）、c-Myc和Notch的积累有关。使用KFC和FBXW7缺陷的人胰腺癌细胞，我们发现Yap沉默减弱了Fbxw7缺失对生长的促进作用。我们的数据表明，Fbxw7是Kras诱导的胰腺肿瘤发生的有效抑制因子，至少部分原因是对Yap的负调控。
