The inflammatory cytokine TNF contributes with RAC3-induced malignant transformation

Authors

  • Mileni Soares Machado Laboratorio de Biología Molecular y Apoptosis, Instituto de Investigaciones Médicas Alfredo Lanari, IDIM-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Combatientes de Malvinas 3150, C1427ARO Buenos Aires, Argentina
  • Francisco D. Rosa Laboratorio de Biología Molecular y Apoptosis, Instituto de Investigaciones Médicas Alfredo Lanari, IDIM-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Combatientes de Malvinas 3150, C1427ARO Buenos Aires, Argentina
  • María C. Lira Laboratorio de Biología Molecular y Apoptosis, Instituto de Investigaciones Médicas Alfredo Lanari, IDIM-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Combatientes de Malvinas 3150, C1427ARO Buenos Aires, Argentina
  • Alejandro J. Urtreger Universidad de Buenos Aires, Instituto de Oncología Ángel H. Roffo, Área Investigación, Av. San Martín 5481, C1417DTB Buenos Aires, Argentina; Member of the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
  • María F. Rubio Laboratorio de Biología Molecular y Apoptosis, Instituto de Investigaciones Médicas Alfredo Lanari, IDIM-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Combatientes de Malvinas 3150, C1427ARO Buenos Aires, Argentina; Member of the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
  • Mónica A. Costas Laboratorio de Biología Molecular y Apoptosis, Instituto de Investigaciones Médicas Alfredo Lanari, IDIM-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Combatientes de Malvinas 3150, C1427ARO Buenos Aires, Argentina; Member of the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) http://orcid.org/0000-0002-4773-3389

DOI:

https://doi.org/10.17179/excli2018-1759

Keywords:

RAC3, cancer stem cells, mesenchymal cells, TNF-malignant transformation

Abstract

RAC3 is a coactivator of steroid receptors and NF-κB. It is usually overexpressed in several tumors, contributes to 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 RAC3 overexpression in the non-tumoral HEK293 cell line.

The study model included the HEK293 tumoral transformed cell line constitutively overexpressing RAC3 by stable transfection and control non-tumoral cells transfected with an empty vector. The HeLa and T47D tumoral cells that 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 molecular mechanisms by which TNF potentiates the RAC3 transforming action, they involve the IKK activation, which in addition induced the β-Catenin transactivation.

Our results demonstrate that although RAC3 overexpression could be a signal strong enough to induce cancer stem cells, the inflammatory microenvironment may be playing a key role contributing to the migratory and invasive phenotype required for metastasis and cancer persistence.

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Published

2018-11-02

How to Cite

Machado, M. S., Rosa, F. D., Lira, M. C., Urtreger, A. J., Rubio, M. F., & Costas, M. A. (2018). The inflammatory cytokine TNF contributes with RAC3-induced malignant transformation. EXCLI Journal, 17, 1030–1042. https://doi.org/10.17179/excli2018-1759

Issue

Vol. 17 (2018)

Section

Original articles

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