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Loss of Notch signaling fosters Barrett’s esophagus development in
c-myc-Cdx1 expressing esophageal cells.
Maria E. Vega, Doug B. Stairs*, Mitsu Natsuizaka, Shinya Ohashi, Hiroshi
Nakagawa, Anil K. Rustgi, Division of Gastroenterology, Abramson Cancer
Center, University of Pennsylvania, Philadelphia, PA, USA, 19104, *Penn State
College of Medicine, Hershey, PA, 17033.
Barrett’s esophagus (BE) is defined as an incomplete intestine metaplasia and a
critical precursor to esophageal adenocarcinoma. The pathological features of
BE are the presence of columnar and goblet cells in the formerly stratified
squamous epithelium of the esophagus. Recently, we have found that Cdx1 and
c-myc are involved in the development of BE metaplasia (Stairs DB et al, PLoS
One 2008). Our previous data show that Notch receptors are downregulated in
human BE samples. Furthermore, Notch signaling is important in the
maintenance of the columnar enterocyte lineage in the small intestine;
conversely, inhibition of Notch signaling favors the secretory cell lineage for the
goblet cell fate. We hypothesize that the lack of Notch signaling in the c-mycCdx1 expressing esophageal epithelial cells will promote further the development
of BE. As a result, we inhibited Notch signaling in esophageal epithelial cells by
the use of a dominant negative mastermind (DN-MAML). Organotypic (3D)
cultures showed a change in the basal layer of the epithelium with columnar cell
morphology and mucin-producing cells. In addition, gene expression analysis
showed increased expression of BE specific genes: Mucin 2, Keratin 8 and
Keratin 20, with suppression of squamous cell specific genes: Keratin 4, Keratin
13. Further analysis reveals that Hath1 and KLF4 are increased with loss of
Notch signaling. We conclude that loss of Notch signaling can promote BE
development further by de-repression of Hath1 and KLF4.
Presently, we are generating a genetic mouse model of BE. Using an EBV-L2
promoter which is specifically expressed in the esophagus and squamous
forestomach, we are expressing Cdx2, c-myc and DN-MAML in these specific
tissues. To this end, we have developed a TetOp inducible L2-myc mouse
model. We have verified the expression of c-myc by IHC.
In aggregate, our dissection of these factors in the development of BE provides
the basis for both prevention and therapeutic strategies.
NCI P01-CA098101 (MEV, MN, SO, HN, AKR), NCI T32 CA-09140 (MEV),