title: Molecular features of the transition from prostatic intraepithelial neoplasia (PIN) to prostate cancer: genome-wide gene-expression profiles of prostate cancers and PINs.
abstract: To characterize the molecular feature in prostate carcinogenesis and the putative transition from prostatic intraepithelial neoplasia (PIN) to invasive prostate cancer (PC), we analyzed gene-expression profiles of 20 PCs and 10 high-grade PINs with a cDNA microarray representing 23,040 genes. Considering the histological heterogeneity of PCs and the minimal nature of PIN lesions, we applied laser microbeam microdissection to purify populations of PC and PIN cells, and then compared their expression profiles with those of corresponding normal prostatic epithelium also purified by laser microbeam microdissection. A hierarchical clustering analysis separated the PC group from the PIN group, except for three tumors that were morphologically defined as one very-high-grade PIN and two low-grade PCs, suggesting that PINs and PCs share some molecular features and supporting the hypothesis of PIN-to-PC transition. On the basis of this hypothesis, we identified 21 up-regulated genes and 63 down-regulated genes commonly in PINs and PCs compared with normal epithelium, which were considered to be involved in the presumably early stage of prostatic carcinogenesis. They included AMACR, OR51E2, RODH, and SMS. Furthermore, we identified 41 up-regulated genes and 98 down-regulated genes in the transition from PINs to PCs; those altered genes, such as POV1, CDKN2C, EPHA4, APOD, FASN, ITGB2, LAMB2, PLAU, and TIMP1, included elements that are likely to be involved in cell adhesion or the motility of invasive PC cells. The down-regulation of EPHA4 by small interfering RNA in PC cells lead to attenuation of PC cell viability. These data provide clues to the molecular mechanisms underlying prostatic carcinogenesis, and suggest candidate genes the products of which might serve as molecular targets for the prevention and treatment of PC.
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Ashida
authors.forename: Hidewaki
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Toyomasa
authors.initials: T
authors.lastname: Katagiri
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Furihata
authors.forename: Megumi
authors.initials: M
authors.lastname: Iiizumi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Anazawa
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Ryo
authors.initials: R
authors.lastname: Takata
authors.forename: Kotaro
authors.initials: K
authors.lastname: Kasahara
authors.forename: Tsuneharu
authors.initials: T
authors.lastname: Miki
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Fujioka
authors.forename: Taro
authors.initials: T
authors.lastname: Shuin
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D002455:Cell Division / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics* / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D036122:Receptor, EphA4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D036122:Receptor, EphA4