The hippo pathway in human upper gastrointestinal dysplasia and carcinoma: a novel oncogenic pathway.
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.


OBJECTIVE
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.


METHODS
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.
Lam-Himlin
Dora M
DM
Department of Pathology, University of Maryland, Baltimore, MD 21201, USA.
Daniels
Jason A
JA
Gayyed
Mariana F
MF
Dong
Jixin
J
Maitra
Anirban
A
Pan
Duojia
D
Montgomery
Elizabeth A
EA
Anders
Robert A
RA
D000230:Adenocarcinoma / Q000378:metabolism* / Q000556:secondary; D001471:Barrett Esophagus / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism* / Q000473:pathology; D007124:Immunoenzyme Techniques; D009687:Nuclear Proteins / Q000378:metabolism*; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000378:metabolism*
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human