Frequent HIN-1 promoter methylation and lack of expression in multiple human tumor types.

TitleFrequent HIN-1 promoter methylation and lack of expression in multiple human tumor types.
Publication TypeJournal Article
Year of Publication2004
AuthorsKrop I, Player A, Tablante A, Taylor-Parker M, Lahti-Domenici J, Fukuoka J, Batra SK, Papadopoulos N, Richards WG, Sugarbaker DJ, Wright RL, Shim J, Stamey TA, Sellers WR, Loda M, Meyerson M, Hruban R, Jen J, Polyak K
JournalMol Cancer Res
Volume2
Issue9
Pagination489-94
Date Published2004 Sep
ISSN1541-7786
KeywordsBody Fluids, Cell Line, Tumor, Cytokines, DNA Methylation, Gene Expression Regulation, Neoplastic, Humans, Lung, Lung Neoplasms, Male, Neoplasms, Pancreas, Pancreatic Neoplasms, Promoter Regions, Genetic, Prostate, Prostatic Neoplasms, Tumor Suppressor Proteins
Abstract

HIN-1 (high in normal-1) is a candidate tumor suppressor identified as a gene silenced by methylation in the majority of breast carcinomas. HIN-1 is highly expressed in the mammary gland, trachea, lung, prostate, pancreas, and salivary gland, and in the lung, its expression is primarily restricted to bronchial epithelial cells. In this report, we show that, correlating with the secretory nature of HIN-1, high levels of HIN-1 protein are detected in bronchial lavage, saliva, plasma, and serum. To determine if, similar to breast carcinomas, HIN-1 is also silenced in tumors originating from other organs with high HIN-1 expression, we analyzed its expression and promoter methylation status in lung, prostate, and pancreatic carcinomas. Nearly all prostate and a significant fraction of lung and pancreatic carcinomas showed HIN-1 hypermethylation, and the majority of lung and prostate tumors lacked HIN-1 expression. In lung carcinomas, the degree of HIN-1 methylation differed among tumor subtypes (P = 0.02), with the highest level of HIN-1 methylation observed in squamous cell carcinomas and the lowest in small cell lung cancer. In lung adenocarcinomas, the expression of HIN-1 correlated with cellular differentiation status. Hypermethylation of the HIN-1 promoter was also frequently observed in normal tissue adjacent to tumors but not in normal tissue from noncancer patients, implying that HIN-1 promoter methylation may be a marker of premalignant changes. Thus, silencing of HIN-1 expression and methylation of its promoter occurs in multiple human cancer types, suggesting that elimination of HIN-1 function may contribute to several forms of epithelial tumorigenesis.

Alternate JournalMol Cancer Res
PubMed ID15383627
Grant ListCA89393 / CA / NCI NIH HHS / United States
CA94787-01 / CA / NCI NIH HHS / United States
R01 CA94074-01A1 / CA / NCI NIH HHS / United States
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Massimo Loda, M.D.

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