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Silencing of Foxp3 delays the growth of murine melanomas and modifies the tumor immunosuppressive environment

Authors Moises Armides Franco-Molina MA, Miranda-Hernández D, Mendoza-Gamboa E, Zapata-Benavides P, Coronado-Cerda E, Sierra-Rivera C, Saavedra-Alonso S, Tamez-Guerra R, Rodríguez-Padilla C

Received 14 June 2015

Accepted for publication 14 October 2015

Published 12 January 2016 Volume 2016:9 Pages 243—253


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Ram Prasad

Peer reviewer comments 3

Editor who approved publication: Dr Faris Farassati

Moisés A Franco-Molina,* Diana F Miranda-Hernández,* Edgar Mendoza-Gamboa, Pablo Zapata-Benavides, Erika E Coronado-Cerda, Crystel A Sierra-Rivera, Santiago Saavedra-Alonso, Reyes S Taméz-Guerra, Cristina Rodríguez-Padilla

Immunology and Virology Department, Biological Sciences Faculty, University Autonoma of Nuevo León (UANL), San Nicolás de los Garza, Nuevo León, Mexico

*These authors contributed equally to this work
Abstract: Forkhead box p3 (Foxp3) expression was believed to be specific for T-regulatory cells but has recently been described in non-hematopoietic cells from different tissue origins and in tumor cells from both epithelial and non-epithelial tissues. The aim of this study was to elucidate the role of Foxp3 in murine melanoma. The B16F10 cell line Foxp3 silenced with small interference Foxp3 plasmid transfection was established and named B16F10.1. These cells had lower levels of Foxp3 mRNA (quantitative real-time reverse transcription-polymerase chain reaction [0.235-fold]), protein (flow cytometry [0.02%]), CD25+ expression (0.06%), cellular proliferation (trypan blue staining), and interleukin (IL)-2 production (enzyme-linked immunosorbent assay [72.35 pg/mL]) than those in B16F10 wild-type (WT) cells (P<0.05). Subcutaneous inoculation of the B16F10.1 cell line into C57BL/6 mice delayed the time of visible tumor appearance, increased the time of survival, and affected the weight of tumors, and also decreased the production of IL-10, IL-2, and transforming growth factor beta compared with mice inoculated with the B16F10 WT cell line. The B16F10.1 cells derived from tumors and free of T-cells (isolated by Dynabeads and plastic attachment) expressed relatively lower levels of Foxp3 and CD25+ than B16F10 WT cells (P<0.05) in a time-dependent manner. The population of tumor-infiltrating lymphocytes of T CD4+ cells (CD4+, CD4+CD25+, and CD4+CD25+Foxp3+) increased in a time-dependent manner (P<0.05) in tumors derived from B16F10 WT cells and decreased in tumors derived from B16F10.1 cells. Similar data were obtained from spleen cells. These results suggest that, in melanomas, Foxp3 partly induces tumor growth by modifying the immune system at the local and peripheral level, shifting the environment toward an immunosuppressive profile. Therapies incorporating this transcription factor could be strategies for cancer treatment.

Keywords: melanoma, Foxp3, cancer, T-regulatory cells

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