The hippo pathway in human upper gastrointestinal dysplasia and carcinoma

A novel oncogenic pathway

Dora M. Lam-Himlin, Jason A. Daniels, Mariana F. Gayyed, Jixin Dong, Anirban Maitra, Duojia Pan, Elizabeth A. Montgomery, Robert A. Anders

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)103-109
Number of pages7
JournalInternational Journal of Gastrointestinal Cancer
Volume37
Issue number4
DOIs
StatePublished - Dec 1 2006

Fingerprint

Stomach
Carcinoma
Stomach Diseases
Carcinogenesis
Proteins
Epithelium
Nuclear Proteins
Growth
Staining and Labeling
Critical Pathways
Drosophila
Hepatocellular Carcinoma
Neoplasms
Cell Survival
Cytoplasm
Adenocarcinoma
Phosphotransferases
Apoptosis
Adenocarcinoma Of Esophagus

Keywords

  • Barrett esophagus
  • Esophageal adenocarcinoma
  • Gastric adenocarcinoma
  • Hippo
  • Yes-associated-protein
  • Yorkie

ASJC Scopus subject areas

  • Gastroenterology
  • Endocrinology
  • Oncology

Cite this

The hippo pathway in human upper gastrointestinal dysplasia and carcinoma : A novel oncogenic pathway. / Lam-Himlin, Dora M.; Daniels, Jason A.; Gayyed, Mariana F.; Dong, Jixin; Maitra, Anirban; Pan, Duojia; Montgomery, Elizabeth A.; Anders, Robert A.

In: International Journal of Gastrointestinal Cancer, Vol. 37, No. 4, 01.12.2006, p. 103-109.

Research output: Contribution to journalArticle

Lam-Himlin, Dora M. ; Daniels, Jason A. ; Gayyed, Mariana F. ; Dong, Jixin ; Maitra, Anirban ; Pan, Duojia ; Montgomery, Elizabeth A. ; Anders, Robert A. / The hippo pathway in human upper gastrointestinal dysplasia and carcinoma : A novel oncogenic pathway. In: International Journal of Gastrointestinal Cancer. 2006 ; Vol. 37, No. 4. pp. 103-109.
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abstract = "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.",
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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.

PY - 2006/12/1

Y1 - 2006/12/1

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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

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KW - Yes-associated-protein

KW - Yorkie

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