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题名: Concomitant loss of EAF2/U19 and Pten synergistically promotes prostate carcinogenesis in the mouse model
作者: 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
通讯作者: Wang, Z (reprint author), Univ Pittsburgh, Sch Med, Dept Urol, Suite G40,5200 Ctr Ave, Pittsburgh, PA 15232 USA.
关键词: prostate cancer ; EAF2/U19 ; Pten ; knockout
刊名: ONCOGENE
发表日期: 2014-05-01
DOI: 10.1038/onc.2013.190
卷: 33, 期:18, 页:2286-2294
收录类别: SCI
文章类型: Article
部门归属: [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
WOS标题词: Science & Technology ; Life Sciences & Biomedicine
资助者: National Institutes of Health Grants [R01 CA 120386, 5 R37 DK51193, 1 P50 CA90386, T32 DK007774]; [P30CA047904]
类目[WOS]: Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
研究领域[WOS]: Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
摘要: 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.
英文摘要: 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.
关键词[WOS]: TUMOR-SUPPRESSOR PTEN ; INTRAEPITHELIAL NEOPLASIA ; SIGNALING PATHWAY ; CELL-SURVIVAL ; CANCER ; MICE ; CARCINOMA ; AKT ; ANGIOGENESIS ; APOPTOSIS
语种: 英语
WOS记录号: WOS:000335451800002
ISSN号: 0950-9232
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.ihb.ac.cn/handle/342005/20100
Appears in Collections:水生生物分子与细胞生物学研究中心_期刊论文

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作者单位: 1.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
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