| First Author | Pu H | Year | 2014 |
| Journal | Carcinogenesis | Volume | 35 |
| Issue | 11 | Pages | 2592-601 |
| PubMed ID | 25173886 | Mgi Jnum | J:216690 |
| Mgi Id | MGI:5609220 | Doi | 10.1093/carcin/bgu183 |
| Citation | Pu H, et al. (2014) PARP-1 regulates epithelial-mesenchymal transition (EMT) in prostate tumorigenesis. Carcinogenesis 35(11):2592-601 |
| abstractText | Poly (ADP-ribose) polymerase (PARP) is involved in key cellular processes such as DNA replication and repair, gene transcription, cell proliferation and apoptosis. The role of PARP-1 in prostate cancer development and progression is not fully understood. The present study investigated the function of PARP-1 in prostate growth and tumorigenesis in vivo. Functional inactivation of PARP-1 by gene-targeted deletion led to a significant reduction in the prostate gland size in young PARP-1-/- mice (6 weeks) compared with wild-type (WT) littermates. To determine the effect of PARP-1 functional loss on prostate cancer onset, PARP-1-/- mice were crossed with the transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Pathological assessment of prostate tumors revealed that TRAMP+/-, PARP-1-/- mice exhibited higher grade prostate tumors compared with TRAMP+/- PARP-1+/+ (16-28 weeks) that was associated with a significantly increased proliferative index and decreased apoptosis among the epithelial cells in TRAMP+/- PARP-1-/- prostate tumors. Furthermore tumors harboring PARP-1 loss, exhibited a downregulation of nuclear androgen receptor. Impairing PARP-1 led to increased levels of transforming growth factor-beta (TGF-beta) and Smads that correlated with induction of epithelial-mesenchymal transition (EMT), as established by loss of E-cadherin and beta-catenin and upregulation of N-cadherin and ZEB-1. Our findings suggest that impaired PARP-1 function promotes prostate tumorigenesis in vivo via TGF-beta-induced EMT. Defining the EMT control by PARP-1 during prostate cancer progression is of translational significance for optimizing PARP-1 therapeutic targeting and predicting response in metastatic castration-resistant prostate cancer. |
