title: CpG hypermethylation of MDR1 gene contributes to the pathogenesis and progression of human prostate cancer.
abstract: Multidrug resistance 1 (MDR1) gene encodes for P-glycoprotein (P-gp), a Mr 170,000 transmembrane calcium-dependent efflux pump that is inactivated in prostate cancer. We hypothesize that inactivation of the MDR1 gene through CpG methylation contributes to the pathogenesis and progression of prostate cancer. To test this hypothesis, CpG methylation status of the MDR1 promoter and its correlation with clinicopathological findings were evaluated in 177 prostate cancer samples and 69 benign prostate hypertrophy (BPH) samples. Cellular proliferation index and apoptotic index were determined by proliferating cell nuclear antigen (PCNA) and single-strand DNA immunostaining, respectively. After 5-aza-2'-deoxycytidine treatment, increased expression of MDR1 mRNA transcript was found in prostate cancer cell lines (DU145, DuPro, and ND1). MDR1 methylation frequency was significantly higher in prostate cancer samples compared with BPH samples (54.8 versus 11.6%, respectively, P < 0.001). Logistic regression analysis revealed that PC patients are 11.5 times more likely to have MDR1 methylation than BPH patients (95% confidence interval 4.87-27.0) and that MDR1 methylation is independent of the age. Significant correlation of MDR1 methylation was observed with high pT category (P < 0.001), high Gleason sum (P = 0.008), high preoperative prostate-specific antigen (P = 0.01), and advancing pathological features. In addition, PCNA-labeling index were significantly higher in methylation-specific PCR (MSP)-positive than in MSP-negative prostate cancer samples (P = 0.048). In contrast, no significant difference in apoptotic index was found between MSP-positive and -negative prostate cancer samples. These findings suggest that CpG hypermethylation of MDR1 promoter is a frequent event in prostate cancer and is related to disease progression via increased cell proliferation in prostate cancer cells.
authors.affiliation: Department of Urology, University of California, San Francisco, California 94121, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Enokida
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiina
authors.forename: Mikio
authors.initials: M
authors.lastname: Igawa
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ogishima
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Kawakami
authors.forename: William W
authors.initials: WW
authors.lastname: Bassett
authors.forename: Jason W
authors.initials: JW
authors.lastname: Anast
authors.forename: Long-Cheng
authors.initials: LC
authors.lastname: Li
authors.forename: Shinji
authors.initials: S
authors.lastname: Urakami
authors.forename: Masaharu
authors.initials: M
authors.lastname: Terashima
authors.forename: Mukesh
authors.initials: M
authors.lastname: Verma
authors.forename: Motoshi
authors.initials: M
authors.lastname: Kawahara
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kane
authors.forename: Peter R
authors.initials: PR
authors.lastname: Carroll
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001483:Base Sequence; D002455:Cell Division / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D000077209:Decitabine; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D020868:Gene Silencing; D019450:Genes, MDR / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger; D000077209:Decitabine; D001374:Azacitidine