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Monoallelic Up-Regulation of the Imprinted H19 Gene in Airway Epithelium of Phenotypically Normal Cigarette Smokers¹

Division of Pulmonary and Critical Care Medicine [R. K., B-G. H., R. G. C.], The Belfer Gene Therapy Core Facility [K. L., A. H., N. R. H., R. G. C.], and Institute of Genetic Medicine [A. H., R. G. C.], Weill Medical College of Cornell University, New York, New York 10021

H19, a paternally imprinted gene, is postulated to have regulatory functions in normal development and oncogenesis. Loss of imprinting (LOI) of H19 is observed in human malignancies, including lung cancer. Microarray assessment of gene expression patterns in airway epithelium of healthy 20 pack-year smokers versus nonsmokers revealed that smokers have dramatically elevated H19 RNA levels without alteration of expression of other imprinted genes. Interestingly, the up-regulation of H19 was not attributable to LOI, i.e., expression of H19 in smokers was monoallelic. These observations suggest that cigarette smoking initially induces up-regulation of the active H19 allele and that there is likely progression to LOI as the burden of smoking increases and as the epithelium undergoes transition from normal to neoplastic. Overexpression and eventual LOI of H19 may represent early markers in the progression of airway epithelium toward lung cancer.

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