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| Author(s): |
Guilherme Oliveira Barbosa
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia |
| Defense date: | 2015-08-31 |
| Examining board members: |
Hernandes Faustino de Carvalho;
Enilza Maria Espreafico;
Claudio Chrysostomo Werneck;
Mário Henrique Bengtson;
Maria Aparecida da Silva Pinhal
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| Advisor: | Hernandes Faustino de Carvalho |
| Abstract | |
Murine ventral prostate (VP) development starts at embryonic day 17.5. Epithelial cells at the urogenital sinus down regulate the expression of Sulfatase-1 and keep the expression of Heparan Sulfate 6-O-sulfotransferase-1 in response to a testosterone peak. This combination increases highly sulfated heparan sulfate (HS) content, which is important for paracrine factors signaling. Heparanase-1 is an endo-beta-D-glucuronidase, responsible for the turnover of HS on vertebrate tissues. Because ventral prostate remodels extracellular matrix during development, we hypothesized that Heparanase-1 and sulfation of HS play a role on postnatal prostate development. To test our hypothesis we used rat ventral prostate organ culture and human normal prostate epithelial (RWPE-1) 3D cell culture on matrigel that mimics acinar morphogenesis. We detected the expression of HS proteoglycans (HSPG), Syndecan and Glipicans on VP during development. Either heparin or Hpse-1 silencing delays epithelial growth, which also resulted in reduction of ERK1/2 signaling. RWPE-1 differentially expressed HSPG during acinar morphogenesis. Chlorate treatment, that reduces sulfation through PAPS synthesis inhibition, abolished RWPE-1 spheroids formation on 3D cell culture. Moreover it impairs epithelial canalization and branching morphogenesis of VP in vitro. Chlorate also increases the expression of Hpse and Mmp-2. SDF-1 partially recovers luminal formation in the low sulfated environment. SDF-1 also promotes spheroid formation and growth while its signaling inhibition with AMD3100 inhibits epithelial cell organization. SDF-1 rescued acinar morphogenesis under chlorate treatment. In conclusion, our results suggests that Heparanase-1 plays a role in early epithelial growth, that sulfation is of great importance for epithelial canalization and branching morphogenesis and that SDF-1 acts on epithelial morphogenesis even at low sulfated environment (AU) | |
| FAPESP's process: | 12/17657-0 - Heparanase activity and its role in the modulation of extracellular signaling in prostate development |
| Grantee: | Guilherme Oliveira Barbosa |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |