Frequent HIN-1 promoter methylation and lack of expression in multiple human tumor types.
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.
Krop
Ian
I
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, D740C, Boston, MA 02115, USA. Kornelia_Polyak@dfci.harvard.edu
Player
Audrey
A
Tablante
Ana
A
Taylor-Parker
Michele
M
Lahti-Domenici
Jaana
J
Fukuoka
Junya
J
Batra
Surinder K
SK
Papadopoulos
Nickolas
N
Richards
William G
WG
Sugarbaker
David J
DJ
Wright
Renee L
RL
Shim
Judy
J
Stamey
Thomas A
TA
Sellers
William R
WR
Loda
Massimo
M
Meyerson
Matthew
M
Hruban
Ralph
R
Jen
Jin
J
Polyak
Kornelia
K
D001826:Body Fluids / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D009369:Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D016207:Cytokines; C434732:SCGB3A1 protein, human; D025521:Tumor Suppressor Proteins