The inflammatory cytokine TNF contribuyes with RAC3-induced malignant transformation

1. MILENI SOARES MACHADO; FRANCISCO D. ROSA; MARÍA C. LIRA; ALEJANDRO J. URTREGER; MARÍA F. RUBIO; MÓNICA A. COSTAS

EXCLI JOURNAL

UNIV MAINZ-MED DEPT

Año: 2018 p. 1030 - 1042

1611-2156

RAC3 is a coactivator of steroid receptors and NF-B. It is usually overexpressed in several tumors, contributesto maintain cancer stem cells and also to induce them when is overexpressed in non-tumoral cells. In this work,we investigated whether the inflammatory cytokine TNF may contribute to the transforming effects of RAC3overexpression in the non-tumoral HEK293 cell line.The study model included the HEK293 tumoral transformed cell line constitutively overexpressing RAC3 by stabletransfection and control non-tumoral cells transfected with an empty vector. The HeLa and T47D tumoral cellsthat naturally overexpress RAC3 were used as positive control.We found that TNF potentiated RAC3-induced mesenchymal transition, involving an increased E-Cadherin downregulation,Vimentin and SNAIL upregulation and enhanced migratory behavior. Moreover, concerning the molecularmechanisms by which TNF potentiates the RAC3 transforming action, they involve the IKK activation,which in addition induced the -Catenin transactivation.Our results demonstrate that although RAC3 overexpression could be a signal strong enough to induce cancer stemcells, the inflammatory microenvironment may be playing a key role contributing to the migratory and invasivephenotype required for metastasis and cancer persistence.