| First Author | Ayala de la Peña F | Year | 2011 |
| Journal | J Biol Chem | Volume | 286 |
| Issue | 23 | Pages | 20778-87 |
| PubMed ID | 21388952 | Mgi Jnum | J:173505 |
| Mgi Id | MGI:5014159 | Doi | 10.1074/jbc.M110.198069 |
| Citation | Ayala de la Pena F, et al. (2011) Loss of p53 and Acquisition of Angiogenic MicroRNA Profile Are Insufficient to Facilitate Progression of Bladder Urothelial Carcinoma in Situ to Invasive Carcinoma. J Biol Chem 286(23):20778-87 |
| abstractText | Activation of oncogenes or inactivation of tumor suppressors in urothelium is considered critical for development of urothelial cancer. Here we report cloning of the urothelium-specific promoter uroplakin-II (UPK II) and generation of transgenic mice in which expression of SV40 large T antigen is driven by UPK II promoter. Inactivation of tumor suppressor p53 and pRb in urothelium by SV40 T antigen resulted in urothelial carcinoma, resembling human high-grade carcinoma in situ. Specific deletion of p53 in urothelial cells using the newly generated UPK II-Cre mice results in normal bladders without any evidence of cancer. The high-grade carcinoma in situ in the UPK II-SV40 mice is associated with significant activation of angiogenic signals consisting of hypoxia-inducible factor-1alpha (HIF-1alpha) and VEGF and a down-regulation of thrombospondin-1. Interestingly, such pro-angiogenic activity was not associated with progression to invasive cancer. Analysis of bladder-associated microRNAs in carcinoma in situ lesions reveals a pro-angiogenic profile, with specific overexpression of miR-18a and miR-19a and down-regulation of miR-107. A group of microRNAs (miRs) identified as associated with invasive human urothelial cancer remained unchanged in this mouse model. Collectively, our results support the notion that activation of angiogenesis and loss of p53 are not sufficient for progression to invasive cancer. Our studies identify a new mouse model for bladder cancer that can be used to study factors that determine progression to an invasive phenotype of bladder cancer. |
