Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types.
TNF-related apoptosis-inducing ligand (TRAIL) selectively induces programmed cell death (apoptosis) in various cancer cells but not in normal cells. TRAIL is known to bind to 4 different receptors, 2 proapoptotic (DR4 and DR5), and 2 potentially antiapoptotic receptors lacking death domains (DcR1 and DcR2). Aberrant promoter methylation and resultant silencing of tumor suppressor genes play an important role in the pathogenesis of many tumor types. Recently aberrant methylation of TRAIL decoy receptors was reported in pediatric tumor cell lines and neuroblastomas. We examined the methylation and expression status of TRAIL receptor genes in cancers of breast, lung, mesothelioma, prostate, bladder, cervix, ovary, brain and in hematopoietic malignancies. Aberrant methylation of DcR1 or DcR2 was present in 70% of primary breast cancers, 31% of primary lung cancers, in 63% of primary malignant mesothelioma (MM), in 60% of prostate cancer, in 42% of bladder cancer, in 100% of cervical cancer, in 43% of ovarian cancer, in 41% of lymphoma, in 26% of leukemia and in 56% of multiple myeloma. Methylation of DR4 and DR5 was rare in all the tumor types examined. Methylation of all the 4 receptors was rare in non malignant tissues. In cell lines, aberrant methylation of DcR1 was present in 11 of 23 (48%) breast, 10 of 27 (37%) lung and 3 of 7 (43%) MM, whereas aberrant methylation of DcR2 was present in 17 of 23 (74%) breast, 13 of 27 (48%) lung and 5 of 7 (71%) MM. The concordance between loss of gene expression and aberrant methylation ranged from 70-100%. Treatment with 5-aza-2'-deoxycytidine restored DcR1 and DcR2 expression in 9 methylated cell lines confirming that aberrant methylation was the cause for silencing of DcR1 and DcR2 expression. Our results demonstrate that DcR1 and DcR2 genes are frequently methylated in various tumor types, and that the role of decoy receptors in tumor pathogenesis needs to be re-evaluated.
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
Narayan
N
Shivapurkar
Shinichi
S
Toyooka
Kiyomi O
KO
Toyooka
Jyotsna
J
Reddy
Kuniharu
K
Miyajima
Makoto
M
Suzuki
Hisayuki
H
Shigematsu
Takao
T
Takahashi
Gunjan
G
Parikh
Harvey I
HI
Pass
Preet M
PM
Chaudhary
Adi F
AF
Gazdar
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation; D058851:GPI-Linked Proteins; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053319:Tumor Necrosis Factor Decoy Receptors
D058851:GPI-Linked Proteins; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; C108661:TNFRSF10C protein, human; C451501:TNFRSF10D protein, human; D053319:Tumor Necrosis Factor Decoy Receptors