Abstract
Loss of heterozygosity (LOH) at chromosome 3p21.3 is one of the most prevalent genetic disturbances occurring at the earliest stage of tumor development for a wide variety of human cancers, culminated in lung cancer. The 19 genes residing at 3p21.3 have been vigorously characterized for tumor suppressor activity and gene inactivation mechanism because of their potentially significant merits of clinical applications. Many of these 19 genes have been shown to manifest various growth inhibitory properties, however none of them are inactivated by coding mutations in their remaining allele as in the Knudson’s two- hits hypothesis. Thus far the most prevailing, alternative gene inactivation mechanism known for the 3p21.3 TSGs is epigenetic silencing by promoter hypermethylation. Previously, we have focused our investigation on one of the 19 genes at 3p21.3, H37/RBM5, and demonstrated its tumor suppressor activity both in vitro and in vivo as well as its mRNA/protein expression loss from the remaining allele in a majority of the primary lung tumors examined. The current study tested our hypothesis that the H37 inactivation in primary lung tumors may, as seen in most of the other 3p21.3 TSGs, be due to hypermethylation in its promoter CpG islands. Contrary to this most plausible postulation, however, we found no evidence of epigenetic gene silencing for the H37 TSG. Here we suggest some of the possible, further- alternative means of the H37 gene expression loss in tumor, including defects in transcription and post-transcriptional/translational modifications as well as mechanisms related to haploinsufficiency.
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Acknowledgment
We are deeply grateful to Mr. and Mrs. Werner and Mimi Wolfen for their abundant and heartfelt support towards lung cancer research which made this study possible. Grant support: Developmental Research Program Award from the University of California at Los Angeles Lung Cancer Specialized Programs of Research Excellence grant P50C A90388 (J.J. Oh), American Lung Association of California Research Grant (J.J. Oh), and the Wolfen Family Lung Cancer Clinical/Translational Research Program at University of California at Los Angeles Jonsson Comprehensive Cancer Center.
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Oh, J.J., Boctor, B.N., Jimenez, C.A. et al. Promoter methylation study of the H37/RBM5 tumor suppressor gene from the 3p21.3 human lung cancer tumor suppressor locus. Hum Genet 123, 55–64 (2008). https://doi.org/10.1007/s00439-007-0449-5
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DOI: https://doi.org/10.1007/s00439-007-0449-5