SMAD3 is essential for transforming growth factor-beta 1-induced urokinase type plasminogen activator expression and migration in transformed keratinocytes
Апстракт
Transforming growth factor-beta 1 (TGF-beta 1) stimulates the extracellular matrix degrading proteases expression and cell migration in order to enhance cancer cells malignancy. In the present study, we analysed the role of TGF-beta 1-induced Smad3 activation in the urokinase type plasminogen activator (uPA) production, as well as in cell migration and E-cadherin downregulation in transformed PDV keratinocyte cell line. TGF-beta 1 signalling was interfered by the chemical inhibitor of the TGF-beta 1-receptor 1 (ALK5), SB505124, and the specific Smad3 inhibitor, SiS3. Our results showed that TGF-beta 1 stimulates uPA expression directly through ALK5 activation. The inhibition of Smad3 strongly reduced the capacity of TGF-beta 1 to stimulate uPA expression, in parallel decreasing the uPA inhibitor plasminogen activator inhibitor type 1 (PAI-1) expression. In addition, the transient expression of dominant negative Smad3 mutant inhibited the TGF-beta 1-induced uPA promoter transactivation.... Moreover, Smad3-/- mouse embryonic fibroblasts were refractory to the induction of uPA by TGF-beta 1. The inhibition of both ALK5 and Smad3 dramatically blocked the TGF-beta 1-stimulated E-cadherin downregulation, F-actin reorganisation and migration of PDV cells. Taken together, our results suggest that the TGF-beta 1-induced activation of Smad3 is the critical step for the uPA upregulation and E-cadherin downregulation, which are the key events preceding the induction of cell migration by TGF-beta 1 in transformed cells.
Кључне речи:
TGF-beta 1 / uPA / PAI-1 / Smad3 / E-cadherin / MigrationИзвор:
European Journal of Cancer, 2012, 48, 10, 1550-1557Издавач:
- Elsevier Sci Ltd, Oxford
Финансирање / пројекти:
- Chile Comision Nacional de Investigacion Cientifica y Tecnologica FONDECYT [1050476]
- Регенеративни и модулаторни потенцијал адултних матичних ћелија (RS-MESTD-Basic Research (BR or ON)-175062)
DOI: 10.1016/j.ejca.2011.06.043
ISSN: 0959-8049
PubMed: 21798735
WoS: 000305278600016
Scopus: 2-s2.0-84862025999
Институција/група
Institut za medicinska istraživanjaTY - JOUR AU - Krstić, Jelena AU - Bugarski, Diana AU - Santibanez, Juan F. PY - 2012 UR - http://rimi.imi.bg.ac.rs/handle/123456789/415 AB - Transforming growth factor-beta 1 (TGF-beta 1) stimulates the extracellular matrix degrading proteases expression and cell migration in order to enhance cancer cells malignancy. In the present study, we analysed the role of TGF-beta 1-induced Smad3 activation in the urokinase type plasminogen activator (uPA) production, as well as in cell migration and E-cadherin downregulation in transformed PDV keratinocyte cell line. TGF-beta 1 signalling was interfered by the chemical inhibitor of the TGF-beta 1-receptor 1 (ALK5), SB505124, and the specific Smad3 inhibitor, SiS3. Our results showed that TGF-beta 1 stimulates uPA expression directly through ALK5 activation. The inhibition of Smad3 strongly reduced the capacity of TGF-beta 1 to stimulate uPA expression, in parallel decreasing the uPA inhibitor plasminogen activator inhibitor type 1 (PAI-1) expression. In addition, the transient expression of dominant negative Smad3 mutant inhibited the TGF-beta 1-induced uPA promoter transactivation. Moreover, Smad3-/- mouse embryonic fibroblasts were refractory to the induction of uPA by TGF-beta 1. The inhibition of both ALK5 and Smad3 dramatically blocked the TGF-beta 1-stimulated E-cadherin downregulation, F-actin reorganisation and migration of PDV cells. Taken together, our results suggest that the TGF-beta 1-induced activation of Smad3 is the critical step for the uPA upregulation and E-cadherin downregulation, which are the key events preceding the induction of cell migration by TGF-beta 1 in transformed cells. PB - Elsevier Sci Ltd, Oxford T2 - European Journal of Cancer T1 - SMAD3 is essential for transforming growth factor-beta 1-induced urokinase type plasminogen activator expression and migration in transformed keratinocytes EP - 1557 IS - 10 SP - 1550 VL - 48 DO - 10.1016/j.ejca.2011.06.043 ER -
@article{ author = "Krstić, Jelena and Bugarski, Diana and Santibanez, Juan F.", year = "2012", abstract = "Transforming growth factor-beta 1 (TGF-beta 1) stimulates the extracellular matrix degrading proteases expression and cell migration in order to enhance cancer cells malignancy. In the present study, we analysed the role of TGF-beta 1-induced Smad3 activation in the urokinase type plasminogen activator (uPA) production, as well as in cell migration and E-cadherin downregulation in transformed PDV keratinocyte cell line. TGF-beta 1 signalling was interfered by the chemical inhibitor of the TGF-beta 1-receptor 1 (ALK5), SB505124, and the specific Smad3 inhibitor, SiS3. Our results showed that TGF-beta 1 stimulates uPA expression directly through ALK5 activation. The inhibition of Smad3 strongly reduced the capacity of TGF-beta 1 to stimulate uPA expression, in parallel decreasing the uPA inhibitor plasminogen activator inhibitor type 1 (PAI-1) expression. In addition, the transient expression of dominant negative Smad3 mutant inhibited the TGF-beta 1-induced uPA promoter transactivation. Moreover, Smad3-/- mouse embryonic fibroblasts were refractory to the induction of uPA by TGF-beta 1. The inhibition of both ALK5 and Smad3 dramatically blocked the TGF-beta 1-stimulated E-cadherin downregulation, F-actin reorganisation and migration of PDV cells. Taken together, our results suggest that the TGF-beta 1-induced activation of Smad3 is the critical step for the uPA upregulation and E-cadherin downregulation, which are the key events preceding the induction of cell migration by TGF-beta 1 in transformed cells.", publisher = "Elsevier Sci Ltd, Oxford", journal = "European Journal of Cancer", title = "SMAD3 is essential for transforming growth factor-beta 1-induced urokinase type plasminogen activator expression and migration in transformed keratinocytes", pages = "1557-1550", number = "10", volume = "48", doi = "10.1016/j.ejca.2011.06.043" }
Krstić, J., Bugarski, D.,& Santibanez, J. F.. (2012). SMAD3 is essential for transforming growth factor-beta 1-induced urokinase type plasminogen activator expression and migration in transformed keratinocytes. in European Journal of Cancer Elsevier Sci Ltd, Oxford., 48(10), 1550-1557. https://doi.org/10.1016/j.ejca.2011.06.043
Krstić J, Bugarski D, Santibanez JF. SMAD3 is essential for transforming growth factor-beta 1-induced urokinase type plasminogen activator expression and migration in transformed keratinocytes. in European Journal of Cancer. 2012;48(10):1550-1557. doi:10.1016/j.ejca.2011.06.043 .
Krstić, Jelena, Bugarski, Diana, Santibanez, Juan F., "SMAD3 is essential for transforming growth factor-beta 1-induced urokinase type plasminogen activator expression and migration in transformed keratinocytes" in European Journal of Cancer, 48, no. 10 (2012):1550-1557, https://doi.org/10.1016/j.ejca.2011.06.043 . .