| First Author | Nam KT | Year | 2012 |
| Journal | Lab Invest | Volume | 92 |
| Issue | 6 | Pages | 883-95 |
| PubMed ID | 22411066 | Mgi Jnum | J:184722 |
| Mgi Id | MGI:5426116 | Doi | 10.1038/labinvest.2012.47 |
| Citation | Nam KT, et al. (2012) Gastric tumor development in Smad3-deficient mice initiates from forestomach/glandular transition zone along the lesser curvature. Lab Invest 92(6):883-95 |
| abstractText | SMAD proteins are downstream effectors of the TGF-beta 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-alpha-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. |
