CDC2/CDK1 expression in esophageal adenocarcinoma and precursor lesions serves as a diagnostic and cancer progression marker and potential novel drug target

Donna E. Hansel, Surajit Dhara, RuChih C. Huang, Raheela Ashfaq, Mari Deasel, Yutaka Shimada, Harold S. Bernstein, John Harmon, Malcolm V Brock, Arlene A. Forastiere, M. Kay Washington, Anirban Maitra, Elizabeth A Montgomery

Research output: Contribution to journalArticle

Abstract

Esophageal adenocarcinoma arises through well-defined precursor lesions (Barrett esophagus), although only a subset of these lesions advances to invasive adenocarcinoma. The lack of markers predicting progression in Barrett esophagus, typical presentation at advanced stage, and limitations of conventional chemotherapy result in >90% mortality for Barrett-associated adenocarcinomas. To identify potential prognostic markers and therapeutic targets, we compared gene expression profiles from Barrett-associated esophageal adenocarcinoma cell lines (BIC1, SEG1, KYAE, OE33) and normal esophageal epithelial scrapings utilizing the Affymetrix U133_A gene expression platform. We identified 560 transcripts with >3-fold up-regulation in the adenocarcinoma cell lines compared with normal epithelium. Utilizing tissue microarrays composed of normal esophageal squamous mucosa (n = 20), Barrett esophagus (n = 10), low-grade dysplasia (n = 14), high-grade dysplasia (n = 27), adenocarcinoma (n = 59), and node metastases (n = 27), we confirmed differential up-regulation of three proteins (Cdc2/Cdk1, Cdc5, and Igfbp3) in adenocarcinomas and Barrett lesions. Protein expression mirrored histologic progression; thus, 87% of low-grade dysplasias had at least focal surface Cdc2/Cdk1 and 20% had >5% surface staining; 96% of high-grade dysplasias expressed abundant surface Cdc2/Cdk1, while invasive adenocarcinoma and metastases demonstrated ubiquitous expression. Esophageal adenocarcinoma cell lines treated with the novel CDC2/CDK1 transcriptional inhibitor, tetra-O-methyl nordihydroguaiaretic acid (EM-1421, formerly named M4N) demonstrated a dose-dependent reduction in cell proliferation, paralleling down-regulation of CDC2/CDK1 transcript and protein levels. These findings suggest a role for CDC2/CDK1 in esophageal adenocarcinogenesis, both as a potential histopathologic marker of dysplasia and a putative treatment target.

Original languageEnglish (US)
Pages (from-to)390-399
Number of pages10
JournalAmerican Journal of Surgical Pathology
Volume29
Issue number3
DOIs
StatePublished - Mar 2005

Fingerprint

Adenocarcinoma
Pharmaceutical Preparations
Neoplasms
Barrett Esophagus
Cell Line
Up-Regulation
CDC2 Protein Kinase
Masoprocol
Neoplasm Metastasis
Transcriptome
Proteins
Down-Regulation
Epithelium
Cell Proliferation
Staining and Labeling
Gene Expression
Drug Therapy
Mortality

Keywords

  • Barrett's esophagus
  • CDC2
  • CDK1
  • Dysplasia
  • EM-1421
  • Esophageal adenocarcinoma
  • Progression marker
  • Transcription inhibitor

ASJC Scopus subject areas

  • Anatomy
  • Pathology and Forensic Medicine

Cite this

CDC2/CDK1 expression in esophageal adenocarcinoma and precursor lesions serves as a diagnostic and cancer progression marker and potential novel drug target. / Hansel, Donna E.; Dhara, Surajit; Huang, RuChih C.; Ashfaq, Raheela; Deasel, Mari; Shimada, Yutaka; Bernstein, Harold S.; Harmon, John; Brock, Malcolm V; Forastiere, Arlene A.; Washington, M. Kay; Maitra, Anirban; Montgomery, Elizabeth A.

In: American Journal of Surgical Pathology, Vol. 29, No. 3, 03.2005, p. 390-399.

Research output: Contribution to journalArticle

Hansel, Donna E. ; Dhara, Surajit ; Huang, RuChih C. ; Ashfaq, Raheela ; Deasel, Mari ; Shimada, Yutaka ; Bernstein, Harold S. ; Harmon, John ; Brock, Malcolm V ; Forastiere, Arlene A. ; Washington, M. Kay ; Maitra, Anirban ; Montgomery, Elizabeth A. / CDC2/CDK1 expression in esophageal adenocarcinoma and precursor lesions serves as a diagnostic and cancer progression marker and potential novel drug target. In: American Journal of Surgical Pathology. 2005 ; Vol. 29, No. 3. pp. 390-399.
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