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The Hippo Pathway in Human Upper Gastrointestinal Dysplasia and Carcinoma: A Novel Oncogenic Pathway

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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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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).

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Authors and Affiliations

  1. Department of Pathology, University of Maryland, 22 South Greene Street, Baltimore, MD, 21201, USA

    Dora M. Lam-Himlin & Duojia Pan

  2. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Jason A. Daniels, Mariana F. Gayyed, Anirban Maitra, Elizabeth A. Montgomery & Robert A. Anders

  3. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Jixin Dong & Duojia Pan

  4. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Anirban Maitra & Robert A. Anders

  5. Division of GI and Liver Pathology, Johns Hopkins School of Medicine, Room 346, Cancer Research Bldg II, 1550 Orleans St., Baltimore, MD, 21231, USA

    Robert A. Anders

Authors
  1. Dora M. Lam-Himlin
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  2. Jason A. Daniels
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  3. Mariana F. Gayyed
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  4. Jixin Dong
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  5. Anirban Maitra
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  6. Duojia Pan
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  7. Elizabeth A. Montgomery
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  8. Robert A. Anders
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Correspondence to Robert A. Anders.

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Lam-Himlin, D.M., Daniels, J.A., Gayyed, M.F. et al. The Hippo Pathway in Human Upper Gastrointestinal Dysplasia and Carcinoma: A Novel Oncogenic Pathway. J Gastrointest Canc 37, 103–109 (2006). https://doi.org/10.1007/s12029-007-0010-8

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  • DOI: https://doi.org/10.1007/s12029-007-0010-8

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