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 | |
刊名 | ONCOGENE |
2014-05-01 | |
卷号 | 33期号:18页码:2286-2294 |
关键词 | prostate cancer EAF2/U19 Pten knockout |
ISSN号 | 0950-9232 |
通讯作者 | Wang, Z (reprint author), Univ Pittsburgh, Sch Med, Dept Urol, Suite G40,5200 Ctr Ave, Pittsburgh, PA 15232 USA. |
中文摘要 | 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. |
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. |
WOS标题词 | Science & Technology ; Life Sciences & Biomedicine |
类目[WOS] | Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity |
研究领域[WOS] | Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity |
关键词[WOS] | TUMOR-SUPPRESSOR PTEN ; INTRAEPITHELIAL NEOPLASIA ; SIGNALING PATHWAY ; CELL-SURVIVAL ; CANCER ; MICE ; CARCINOMA ; AKT ; ANGIOGENESIS ; APOPTOSIS |
收录类别 | SCI |
资助信息 | National Institutes of Health Grants [R01 CA 120386, 5 R37 DK51193, 1 P50 CA90386, T32 DK007774]; [P30CA047904] |
语种 | 英语 |
WOS记录号 | WOS:000335451800002 |
公开日期 | 2014-08-13 |
内容类型 | 期刊论文 |
源URL | [http://ir.ihb.ac.cn/handle/342005/20100] |
专题 | 水生生物研究所_水生生物分子与细胞生物学研究中心_期刊论文 |
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 |
推荐引用方式 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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