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(Chest. 2002;121:27S-28S.)
© 2002 American College of Chest Physicians

Molecular and Physiologic Evidence for 5'CpG Island Methylation of the Endothelin B Receptor Gene in Lung Cancer*

Andrea J. Cohen, MD; Steven Belinsky, MD; Wilbur Franklin, MD and Scott Beard, MSc

* From the Division of Pulmonary Science and Critical Care Medicine (Drs. Cohen and Franklin, and Mr. Beard), Denver Veterans Affairs Medical Center and University of Colorado Health Sciences Center; and Lovelace Research Institute (Dr. Belinsky), Albuquerque, NM.

Correspondence to: Andrea J. Cohen, MD, Assistant Professor of Medicine, Denver VA Medical Center, University of Colorado Health Sciences Center, 1055 Clermont Ave., Resp 111A, Denver, CO 80220

We have previously reported molecular and physiologic evidence for an endothelin-1 autocrine loop in lung cancer. The endothelin-B receptor (ETBR), which is believed to counter-regulate endothelin-1, is not expressed in the majority of lung cancer cell lines.

We hypothesized that the inactivation of the ETBR is due to epigenetic silencing, specifically the hypermethylation of cytosine nucleotides of the 5CpG "island" surrounding the transcriptional start region of the ETBR gene. This process has been associated with the silencing of a number of tumor-suppressor genes.

Bisulfite sequencing of the ETBR promoter region revealed that the 5'CpG island of the A549 cell line was methylated. Using a novel methylation-specific polymerase chain reaction assay, ETBR was determined to be methylated in six of eight small cell lung carcinoma cell lines, five of six adenocarcinoma cell lines, zero of two large cell carcinoma cell lines, and two of two squamous cell lines. Methylation was not detected in two bronchial epithelial cell lines. In the lung tumors tested, seven of nine adenocarcinomas, one of one large cell carcinoma, two of three squamous cell cancers, and zero of one carcinoid tumors were positive for ETBR methylation. Treatment with 5-Aza-2 deoxycytidine (the inhibitor of DNA methylation) and trichostatin A (the inhibitor of histone deacetylase) induced the re-expression of ETBR by reverse transcriptase-polymerase chain reaction in several lung cancer cell lines. Hypermethylation of the 5'CpG island "encompassing" the transcriptional regulatory region of the ETBR gene may be an important gene-inactivating event of ETBR in lung cancer. We are currently testing the feasibility of using the ETBR methylation assay in the early detection of lung cancer in high-risk patients.


   Footnotes
 
Abbreviation: ETBR = endothelin-B receptor

This research was supported by a Veterans Affairs Advanced Career Development Award and by APS Giles Filley Memorial Award.





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