title: CDC2/CDK1 expression in esophageal adenocarcinoma and precursor lesions serves as a diagnostic and cancer progression marker and potential novel drug target.
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.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Donna E
authors.initials: DE
authors.lastname: Hansel
authors.forename: Surajit
authors.initials: S
authors.lastname: Dhara
authors.forename: RuChih C
authors.initials: RC
authors.lastname: Huang
authors.forename: Raheela
authors.initials: R
authors.lastname: Ashfaq
authors.forename: Mari
authors.initials: M
authors.lastname: Deasel
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimada
authors.forename: Harold S
authors.initials: HS
authors.lastname: Bernstein
authors.forename: John
authors.initials: J
authors.lastname: Harmon
authors.forename: Malcolm
authors.initials: M
authors.lastname: Brock
authors.forename: Arlene
authors.initials: A
authors.lastname: Forastiere
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Montgomery
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D001471:Barrett Esophagus / Q000378:metabolism* / Q000473:pathology; D016203:CDC2 Protein Kinase / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D004947:Esophagus / Q000033:anatomy & histology / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D009637:Masoprocol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011230:Precancerous Conditions / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis; D046888:Tissue Array Analysis
chemical_list: D018797:Cell Cycle Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C076852:terameprocol; D009637:Masoprocol; D016203:CDC2 Protein Kinase