title: Elevation of WNT5A expression in polyp formation in Lkb1+/- mice and Peutz-Jeghers syndrome.
abstract: 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.
authors.affiliation: 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.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lai
authors.forename: James
authors.initials: J
authors.lastname: Robinson
authors.forename: Sue
authors.initials: S
authors.lastname: Clark
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.forename: Richard
authors.initials: R
authors.lastname: Poulsom
authors.forename: Andrew
authors.initials: A
authors.lastname: Silver
mesh_terms: D000818:Animals; D005753:Gastric Mucosa / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010580:Peutz-Jeghers Syndrome / Q000235:genetics / Q000378:metabolism*; D011127:Polyps / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D015398:Signal Transduction; D013272:Stomach Diseases / Q000378:metabolism; D051153:Wnt Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D000071818:Wnt-5a Protein
chemical_list: D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse