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Concomitant loss of EAF2/U19 and Pten synergistically promotes prostate carcinogenesis in the mouse model
Ai, J.1; Pascal, L. E.1; O'Malley, K. J.1; Dar, J. A.1; Isharwal, S.1; Qiao, Z.2; Ren, B.1; Rigatti, L. H.3; Dhir, R.4; Xiao, W.5; Nelson, J. B.1; Wang, Z.1,6,7; Wang, Z (reprint author), Univ Pittsburgh, Sch Med, Dept Urol, Suite G40,5200 Ctr Ave, Pittsburgh, PA 15232 USA.
2014-05-01
Source PublicationONCOGENE
ISSN0950-9232
Volume33Issue:18Pages:2286-2294
AbstractMultiple genetic alterations are associated with prostate carcinogenesis. Tumor-suppressor genes phosphatase and tensin homolog deleted on chromosome 10 (Pten) and androgen upregulated gene 19 (U19), which encodes ELL-associated factor 2 (EAF2), are frequently inactivated or downregulated in advanced prostate cancers. Previous studies showed that EAF2 knockout caused tumors in multiple organs and prostatic intraepithelial neoplasia (PIN) in mice. However, EAF2-knockout mice did not develop prostate cancer even at 2 years of age. To further define the roles of EAF2 in prostate carcinogenesis, we crossed the Pten +/- and EAF2 +/- mice in the C57/BL6 background to generate EAF2 -/- Pten +/-, Pten +/-, EAF2 -/- and wild-type mice. The prostates from virgin male mice with the above four genotypes were analyzed at 7 weeks, 19 weeks and 12 months of age. Concomitant loss of EAF2 function and inactivation of one Pten allele induced spontaneous prostate cancer in 33% of the mice. Prostatic tissues from intact EAF2 -/- Pten +/- mice exhibited higher levels of phospho-Akt, -p44/42 and microvessel density. Moreover, phospho-Akt remained high after castration. Consistently, there was a synergistic increase in prostate epithelial proliferation in both intact and castrated EAF2 -/- Pten +/- mice. Using laser-capture microdissection coupled with real-time reverse transcription-PCR, we confirmed that co-downregulation of EAF2 and Pten occurred in > 50% clinical prostate cancer specimens with Gleason scores of 8-9 (n = 11), which is associated with poor prognosis. The above findings together demonstrated synergistic functional interactions and clinical relevance of concurrent EAF2 and Pten downregulation in prostate carcinogenesis.; Multiple genetic alterations are associated with prostate carcinogenesis. Tumor-suppressor genes phosphatase and tensin homolog deleted on chromosome 10 (Pten) and androgen upregulated gene 19 (U19), which encodes ELL-associated factor 2 (EAF2), are frequently inactivated or downregulated in advanced prostate cancers. Previous studies showed that EAF2 knockout caused tumors in multiple organs and prostatic intraepithelial neoplasia (PIN) in mice. However, EAF2-knockout mice did not develop prostate cancer even at 2 years of age. To further define the roles of EAF2 in prostate carcinogenesis, we crossed the Pten +/- and EAF2 +/- mice in the C57/BL6 background to generate EAF2 -/- Pten +/-, Pten +/-, EAF2 -/- and wild-type mice. The prostates from virgin male mice with the above four genotypes were analyzed at 7 weeks, 19 weeks and 12 months of age. Concomitant loss of EAF2 function and inactivation of one Pten allele induced spontaneous prostate cancer in 33% of the mice. Prostatic tissues from intact EAF2 -/- Pten +/- mice exhibited higher levels of phospho-Akt, -p44/42 and microvessel density. Moreover, phospho-Akt remained high after castration. Consistently, there was a synergistic increase in prostate epithelial proliferation in both intact and castrated EAF2 -/- Pten +/- mice. Using laser-capture microdissection coupled with real-time reverse transcription-PCR, we confirmed that co-downregulation of EAF2 and Pten occurred in > 50% clinical prostate cancer specimens with Gleason scores of 8-9 (n = 11), which is associated with poor prognosis. The above findings together demonstrated synergistic functional interactions and clinical relevance of concurrent EAF2 and Pten downregulation in prostate carcinogenesis.
SubtypeArticle
KeywordProstate Cancer Eaf2/u19 Pten Knockout
Department[Ai, J.; Pascal, L. E.; O'Malley, K. J.; Dar, J. A.; Isharwal, S.; Ren, B.; Nelson, J. B.; Wang, Z.] Univ Pittsburgh, Sch Med, Dept Urol, Pittsburgh, PA 15232 USA; [Qiao, Z.] Harbin Med Univ, Affiliated Hosp 3, Dept Urol, Harbin, Peoples R China; [Rigatti, L. H.] Univ Pittsburgh, Sch Med, Div Lab Anim Resources, Pittsburgh, PA 15232 USA; [Dhir, R.] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15232 USA; [Xiao, W.] Chinese Acad Sci, Inst Hydrobiol, Wuhan, Peoples R China; [Wang, Z.] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15232 USA; [Wang, Z.] Univ Pittsburgh, Sch Med, Inst Canc, Pittsburgh, PA 15232 USA
DOI10.1038/onc.2013.190
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
Funding OrganizationNational Institutes of Health Grants [R01 CA 120386, 5 R37 DK51193, 1 P50 CA90386, T32 DK007774]; [P30CA047904] ; National Institutes of Health Grants [R01 CA 120386, 5 R37 DK51193, 1 P50 CA90386, T32 DK007774]; [P30CA047904] ; National Institutes of Health Grants [R01 CA 120386, 5 R37 DK51193, 1 P50 CA90386, T32 DK007774]; [P30CA047904] ; National Institutes of Health Grants [R01 CA 120386, 5 R37 DK51193, 1 P50 CA90386, T32 DK007774]; [P30CA047904]
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
WOS SubjectBiochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
WOS IDWOS:000335451800002
WOS KeywordTUMOR-SUPPRESSOR PTEN ; INTRAEPITHELIAL NEOPLASIA ; SIGNALING PATHWAY ; CELL-SURVIVAL ; CANCER ; MICE ; CARCINOMA ; AKT ; ANGIOGENESIS ; APOPTOSIS
Funding OrganizationNational Institutes of Health Grants [R01 CA 120386, 5 R37 DK51193, 1 P50 CA90386, T32 DK007774]; [P30CA047904] ; National Institutes of Health Grants [R01 CA 120386, 5 R37 DK51193, 1 P50 CA90386, T32 DK007774]; [P30CA047904] ; National Institutes of Health Grants [R01 CA 120386, 5 R37 DK51193, 1 P50 CA90386, T32 DK007774]; [P30CA047904] ; National Institutes of Health Grants [R01 CA 120386, 5 R37 DK51193, 1 P50 CA90386, T32 DK007774]; [P30CA047904]
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Cited Times:17[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.ihb.ac.cn/handle/342005/20100
Collection水生生物分子与细胞生物学研究中心_期刊论文
Corresponding AuthorWang, Z (reprint author), Univ Pittsburgh, Sch Med, Dept Urol, Suite G40,5200 Ctr Ave, Pittsburgh, PA 15232 USA.
Affiliation1.Univ Pittsburgh, Sch Med, Dept Urol, Pittsburgh, PA 15232 USA
2.Harbin Med Univ, Affiliated Hosp 3, Dept Urol, Harbin, Peoples R China
3.Univ Pittsburgh, Sch Med, Div Lab Anim Resources, Pittsburgh, PA 15232 USA
4.Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15232 USA
5.Chinese Acad Sci, Inst Hydrobiol, Wuhan, Peoples R China
6.Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15232 USA
7.Univ Pittsburgh, Sch Med, Inst Canc, Pittsburgh, PA 15232 USA
Recommended Citation
GB/T 7714
Ai, J.,Pascal, L. E.,O'Malley, K. J.,et al. Concomitant loss of EAF2/U19 and Pten synergistically promotes prostate carcinogenesis in the mouse model[J]. ONCOGENE,2014,33(18):2286-2294.
APA Ai, J..,Pascal, L. E..,O'Malley, K. J..,Dar, J. A..,Isharwal, S..,...&Wang, Z .(2014).Concomitant loss of EAF2/U19 and Pten synergistically promotes prostate carcinogenesis in the mouse model.ONCOGENE,33(18),2286-2294.
MLA Ai, J.,et al."Concomitant loss of EAF2/U19 and Pten synergistically promotes prostate carcinogenesis in the mouse model".ONCOGENE 33.18(2014):2286-2294.
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