Colorectal Cancer Genetics, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, Whitechapel, London, UK.
J Pathol. 2011 Apr;223(5):584-92. doi: 10.1002/path.2835. Epub 2011 Feb 21.
Peutz-Jeghers syndrome (PJS) is a rare, inherited disease caused by germline mutation of the LKB1 gene. Patients with PJS develop characteristic polyps in the digestive tract and carry an elevated risk of cancers in multiple organs, including the intestinal tract. While LKB1 is capable of phosphorylating AMPK and regulates the mTOR pathway, it is also known to be a multitasking protein that can influence other cellular processes, including cell polarity. We hypothesized that there may be other biological pathways directly or indirectly affected by the loss of LKB1 in PJS and aimed to investigate this possibility through transcriptional profiling of polyps harvested from an Lkb1(+/-) mouse model of PJS and from PJS patients. We identified alterations in the mRNA level of a wide range of genes, including some that are involved in Wnt signalling (Wnt5a, Wif1, Dixdc1, Wnt11, Ccnd1, and Ccnd2), although we did not observe nuclear localization of β-catenin in over 93 human PJS intestinal polyps or in 24 gastric polyps from Lkb1(+/-) mice. Among these genes, WNT5A, a non-canonical and non-transforming Wnt, is consistently up-regulated in both Lkb1(+/-) mice and human PJS polyps at a high level. We performed in situ hybridization to further define the spatial expression pattern of WNT5A and observed a strong signal in the stroma of mouse and human polyps compared to no or very low expression in the mucosa. Our findings indicate that WNT5A plays an important role in PJS polyposis.
Peutz-Jeghers 综合征（PJS）是一种罕见的遗传性疾病，由 LKB1 基因的种系突变引起。PJS 患者在消化道中会出现特征性的息肉，并携带多个器官（包括肠道）癌症的高风险。虽然 LKB1 能够磷酸化 AMPK 并调节 mTOR 通路，但它也是一种多功能蛋白，能够影响其他细胞过程，包括细胞极性。我们假设，在 PJS 中，LKB1 的缺失可能会直接或间接地影响其他生物学途径，并旨在通过对来自 PJS 患者和 Lkb1(+/-)小鼠模型的息肉进行转录谱分析来研究这种可能性。我们发现，广泛的基因的 mRNA 水平发生了改变，包括一些参与 Wnt 信号通路的基因（Wnt5a、Wif1、Dixdc1、Wnt11、Ccnd1 和 Ccnd2），尽管我们没有观察到超过 93 个人类 PJS 肠道息肉或 24 个 Lkb1(+/-)小鼠胃息肉中β-catenin 的核定位。在这些基因中，WNT5A 是一种非经典的非转化 Wnt，在 Lkb1(+/-)小鼠和人类 PJS 息肉中均持续高表达。我们进行了原位杂交实验，以进一步确定 WNT5A 的空间表达模式，并观察到与粘膜相比，在小鼠和人类息肉的基质中信号较强。我们的研究结果表明，WNT5A 在 PJS 息肉形成中起着重要作用。
