title: Gastric tumor development in Smad3-deficient mice initiates from forestomach/glandular transition zone along the lesser curvature.
abstract: SMAD proteins are downstream effectors of the TGF-β signaling pathway. Smad3-null mice develop colorectal cancer by 6 months of age. In this study, we have examined whether the loss of Smad3 promotes gastric neoplasia in mice. The stomachs of Smad3⁻/⁻ mice were compared with age-matched Smad3 heterozygous and wild-type mice. E-cadherin, Ki-67, phosphoSTAT3, and TFF2/SP expression was analyzed by immunohistochemisty. The short hairpin RNA (ShRNA)-mediated knockdown of Smad3 in AGS and MKN28 cells was also performed. In addition, we examined alterations in DCLK1-expressing cells. Smad3⁻/⁻ mouse stomachs at 6 months of age revealed the presence of exophytic growths along the lesser curvature in the proximal fundus. Six-month-old Smad3⁻/⁻ mouse stomachs showed metaplastic columnar glands initiating from the transition zone junction between the forestomach and the glandular epithelium along the lesser curvature. Ten-month-old Smad3⁻/⁻ mice all exhibited invasive gastric neoplastic changes with increased Ki-67, phosphoSTAT3 expression, and aberrant cytosolic E-cadherin staining in papillary glands within the invading submucosal gland. The shRNA-mediated knockdown of Smad3 in AGS and MKN28 cells promoted the expression of phosphoSTAT3. DCLK1-expressing cells, which also stained for the tuft cell marker acetylated-α-tubulin, were observed in 10-month-old Smad3⁻/⁻ mice within tumors and in fundic invasive lesions. In conclusion, Smad3-null mice develop gastric tumors in the fundus, which arise from the junction between the forestomach and the glandular epithelium and progress to prominent invasive tumors over time. Smad3-null mice represent a novel model of fundic gastric tumor initiated from forestomach/glandular transition zone along the lesser curvature.
authors.affiliation: Nashville Department of Veterans Affairs Medical Center, Vanderbilt University School of Medicine, Nashville, TN, USA. ki.t.nam@vanderbilt.edu
authors.forename: Ki Taek
authors.initials: KT
authors.lastname: Nam
authors.forename: Ryan
authors.initials: R
authors.lastname: O'Neal
authors.forename: Yeo Song
authors.initials: YS
authors.lastname: Lee
authors.forename: Yong Chan
authors.initials: YC
authors.lastname: Lee
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Coffey
authors.forename: James R
authors.initials: JR
authors.lastname: Goldenring
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D000089742:Doublecortin-Like Kinases; D004943:Esophagogastric Junction / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005748:Gastric Fundus / Q000378:metabolism / Q000473:pathology*; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology*; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D051900:Smad3 Protein / Q000172:deficiency*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D000071164:Trefoil Factor-2
chemical_list: D014408:Biomarkers, Tumor; D050796:STAT3 Transcription Factor; D051900:Smad3 Protein; C494087:Stat3 protein, mouse; C000604007:TFF2 protein, human; D000071164:Trefoil Factor-2; D000089742:Doublecortin-Like Kinases; C485525:Dclk1 protein, mouse; D017346:Protein Serine-Threonine Kinases