TY - JOUR
T1 - The hippo pathway in human upper gastrointestinal dysplasia and carcinoma
T2 - A novel oncogenic pathway
AU - Lam-Himlin, Dora M.
AU - Daniels, Jason A.
AU - Gayyed, Mariana F.
AU - Dong, Jixin
AU - Maitra, Anirban
AU - Pan, Duojia
AU - Montgomery, Elizabeth A.
AU - Anders, Robert A.
N1 - Funding Information:
Acknowledgements This work was supported by grants from the National Institutes of Health to D.J.P. (EY015708), A.M. (R01CA113669 and R21DK072532), and R.A.A. (DK067187).
PY - 2006/12
Y1 - 2006/12
N2 - Background: The Hippo (Hpo) pathway is highly conserved in humans and was originally uncovered in Drosophila as a potent regulator of inhibiting cell growth and promoting apoptosis. The Hippo pathway consists of a tumor suppressor kinase cascade that negatively regulates growth and results in inactivation of a transcriptional co-activator, Yorkie (yki). The human ortholog of Yki, the yes-associated protein (YAP), has a 31% sequence identity and similar biologic activity. The potential role of YAP in tumorigenesis was also reported in a murine genetic screen which identified a genomic amplification of YAP in hepatocellular carcinoma. Aim: Given this pathway's critical control of cell growth, survival, proliferation, and amplification in malignancy, we wanted to explore the possible role of the Hippo pathway in human esophageal and gastric tumorigenesis. Method: The expression of YAP was evaluated with immunolabeling of esophageal and gastric tissue microarrays from 169 patients, with nondysplastic, dysplastic, and malignant foci represented. Cytoplasmic and nuclear staining were scored as 0 = none, 1 < 10%, 2 = 10-50%, and 3 > 50% for the nonneoplastic, dysplastic, and malignant epithelium. Multiple scores were averaged for each patient. Expression of YAP could be seen in the proliferating compartments of nonneoplastic tissue. Results: Compared to nonneoplastic epithelium, there was a significant increase in YAP cytoplasmic and nuclear localization in high-grade dysplastic epithelium and adenocarcinoma of the esophagus. There was also a significant increase in YAP cytoplasmic and nuclear staining of gastric carcinoma and metastatic gastric disease compared to nonneoplastic gastric tissue. Conclusions: YAP expression in the cytoplasm and nucleus is significantly increased in high-grade dysplasia and adenocarcinoma of the esophagus as well as gastric adenocarcinoma and metastatic gastric disease, suggesting a role for this recently uncovered pathway in esophageal and gastric epithelial tumorigenesis.
AB - Background: The Hippo (Hpo) pathway is highly conserved in humans and was originally uncovered in Drosophila as a potent regulator of inhibiting cell growth and promoting apoptosis. The Hippo pathway consists of a tumor suppressor kinase cascade that negatively regulates growth and results in inactivation of a transcriptional co-activator, Yorkie (yki). The human ortholog of Yki, the yes-associated protein (YAP), has a 31% sequence identity and similar biologic activity. The potential role of YAP in tumorigenesis was also reported in a murine genetic screen which identified a genomic amplification of YAP in hepatocellular carcinoma. Aim: Given this pathway's critical control of cell growth, survival, proliferation, and amplification in malignancy, we wanted to explore the possible role of the Hippo pathway in human esophageal and gastric tumorigenesis. Method: The expression of YAP was evaluated with immunolabeling of esophageal and gastric tissue microarrays from 169 patients, with nondysplastic, dysplastic, and malignant foci represented. Cytoplasmic and nuclear staining were scored as 0 = none, 1 < 10%, 2 = 10-50%, and 3 > 50% for the nonneoplastic, dysplastic, and malignant epithelium. Multiple scores were averaged for each patient. Expression of YAP could be seen in the proliferating compartments of nonneoplastic tissue. Results: Compared to nonneoplastic epithelium, there was a significant increase in YAP cytoplasmic and nuclear localization in high-grade dysplastic epithelium and adenocarcinoma of the esophagus. There was also a significant increase in YAP cytoplasmic and nuclear staining of gastric carcinoma and metastatic gastric disease compared to nonneoplastic gastric tissue. Conclusions: YAP expression in the cytoplasm and nucleus is significantly increased in high-grade dysplasia and adenocarcinoma of the esophagus as well as gastric adenocarcinoma and metastatic gastric disease, suggesting a role for this recently uncovered pathway in esophageal and gastric epithelial tumorigenesis.
KW - Barrett esophagus
KW - Esophageal adenocarcinoma
KW - Gastric adenocarcinoma
KW - Hippo
KW - Yes-associated-protein
KW - Yorkie
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U2 - 10.1007/s12029-007-0010-8
DO - 10.1007/s12029-007-0010-8
M3 - Article
C2 - 18175224
AN - SCOPUS:43149110395
SN - 1537-3649
VL - 37
SP - 103
EP - 109
JO - International Journal of Gastrointestinal Cancer
JF - International Journal of Gastrointestinal Cancer
IS - 4
ER -