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

被引：77

作者：

Lam-Himlin D.M. ^{[1
]}

Daniels J.A. ^{[2
]}

Gayyed M.F. ^{[2
]}

Dong J. ^{[3
]}

Maitra A. ^{[2
,4
]}

Pan D. ^{[1
,3
]}

Montgomery E.A. ^{[2
]}

Anders R.A. ^{[2
,4
,5
]}

机构：

[1] Department of Pathology, University of Maryland, Baltimore, MD 21201

[2] Department of Pathology, Johns Hopkins University School of Medicine, Baltimore

[3] Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore

[4] Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore

[5] Division of GI and Liver Pathology, Johns Hopkins School of Medicine, Cancer Research Bldg. II, Baltimore, MD 21231

来源：

Journal of Gastrointestinal Cancer | 2006年 / 37卷 / 4期

基金：

美国国家卫生研究院;

关键词：

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

D O I：

10.1007/s12029-007-0010-8

中图分类号：

学科分类号：

摘要：

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. © 2007 Humana Press Inc.

引用

页码：103 / 109

页数：6

共 20 条

[1]

Jemal A., Tiwari R.C., Murray T., Ghafoor A., Samuels A., Ward E., Et al., Cancer statistics, 2004, CA Cancer J Clin, 54, pp. 8-29, (2004)

[2]

Brown L.M., Devesa S.S., Epidemiologic trends in esophageal and gastric cancer in the United States, Surg Oncol Clin N Am, 11, pp. 235-256, (2002)

[3]

Lagergren J., Bergstrom R., Lindgren A., Nyren O., Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma, N Engl J Med, 340, pp. 825-831, (1999)

[4]

Enzinger P.C., Mayer R.J., Esophageal cancer, N Engl J Med, 349, pp. 2241-2252, (2003)

[5]

Buttar N.S., Wang K.K., Sebo T.J., Riehle D.M., Krishnadath K.K., Lutzke L.S., Et al., Extent of high-grade dysplasia in Barrett's esophagus correlates with risk of adenocarcinoma, Gastroenterology, 120, pp. 1630-1639, (2001)

[6]

Conio M., Blanchi S., Lapertosa G., Ferraris R., Sablich R., Marchi S., Et al., Long-term endoscopic surveillance of patients with Barrett's esophagus. Incidence of dysplasia and adenocarcinoma: A prospective study, Am J Gastroenterol, 98, pp. 1931-1939, (2003)

[7]

Montgomery E., Bronner M.P., Goldblum J.R., Greenson J.K., Haber M.M., Hart J., Et al., Reproducibility of the diagnosis of dysplasia in Barrett esophagus: A reaffirmation, Hum Pathol, 32, pp. 368-378, (2001)

[8]

Reid B.J., Levine D.S., Longton G., Blount P.L., Rabinovitch P.S., Predictors of progression to cancer in Barrett's esophagus: Baseline histology and flow cytometry identify low- and high-risk patient subsets, Am J Gastroenterol, 95, pp. 1669-1676, (2000)

[9]

Weston A.P., Sharma P., Topalovski M., Richards R., Cherian R., Dixon A., Et al., Long-term follow-up of Barrett's high-grade dysplasia, Am J Gastroenterol, 95, pp. 1888-1893, (2000)

[10]

Crew K.D., Neugut A.I., Epidemiology of upper gastrointestinal malignancies, Semin Oncol, 31, pp. 450-464, (2004)

← 1 2 →