title: Juvenile polyps have gastric differentiation with MUC5AC expression and downregulation of CDX2 and SMAD4.
abstract: CDX2 is a homeobox transcription factor that works as a master gene in intestinal differentiation, both in the colon and in aberrant locations such as intestinal metaplasia (IM) of the stomach. Transgenic mice with Cdx2 expression in the stomach develop IM and Cdx2(+/-) mice develop hamartomatous polyps in the colon presenting gastric differentiation. We previously observed regulation of CDX2 by the BMP/SMAD pathway in the gastric context. Here, we hypothesized that juvenile polyps, which are hamartomatous polyps caused by mutations in members of the BMP/SMAD pathway, might recapitulate the gastric differentiation observed in Cdx2(+/-) mice due to SMAD4 and CDX2 downregulation. We characterized SMAD4 and CDX2 expression in a series of 18 solitary juvenile polyps and 2 polyps from juvenile polyposis (JP) patients, one with a germline SMAD4 mutation and one with a germline BMPRIA mutation, as well as the expression of an intestinal differentiation marker, MUC2 (by immunohistochemistry and in situ hybridization), and gastric differentiation markers, MUC5AC and MUC6 (by immunohistochemistry). We observed that juvenile polyps have a heterogeneous expression of CDX2, MUC2 and SMAD4, with negative areas, and 15 of the 18 solitary polyps and the JP case with SMAD4 mutation exhibit de novo expression of MUC5AC but not MUC6. In conclusion, juvenile polyps have gastric transdifferentiation associated with downregulation of CDX2 and SMAD4, lending support to the role of the BMP/SMAD pathway in CDX2 regulation.
authors.affiliation: IPATIMUP, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Dr. Roberto Frias si/na, 4200 Porto, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Barros
authors.forename: Nuno
authors.initials: N
authors.lastname: Mendes
authors.forename: James R
authors.initials: JR
authors.lastname: Howe
authors.forename: Celso A
authors.initials: CA
authors.lastname: Reis
authors.forename: Carme
authors.initials: C
authors.lastname: de Bolos
authors.forename: Fátima
authors.initials: F
authors.lastname: Carneiro
authors.forename: Leonor
authors.initials: L
authors.lastname: David
authors.forename: Raquel
authors.initials: R
authors.lastname: Almeida
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D000071616:CDX2 Transcription Factor; D054338:Cell Transdifferentiation; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D044483:Intestinal Polyposis / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D055271:Mucin 5AC / Q000378:metabolism*; D055262:Mucin-2 / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D013270:Stomach / Q000473:pathology*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; C524625:MUC2 protein, human; D055271:Mucin 5AC; D055262:Mucin-2; C497796:SMAD4 protein, human; D051901:Smad4 Protein