Oncotarget

Research Papers:

Glypican-3 induces a mesenchymal to epithelial transition in human breast cancer cells

Lilian Fedra Castillo, Rocío Tascón, María Amparo Lago Huvelle, Gisela Novack, María Candelaria Llorens, Ancely Ferreira dos Santos, Jorge Shortrede, Ana María Cabanillas, Elisa Bal de Kier Joffé, Leticia Labriola and María Giselle Peters _

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Oncotarget. 2016; 7:60133-60154. https://doi.org/10.18632/oncotarget.11107

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Abstract

Lilian Fedra Castillo1,*, Rocío Tascón1, María Amparo Lago Huvelle2,*, Gisela Novack1, María Candelaria Llorens3,*, Ancely Ferreira dos Santos4, Jorge Shortrede1, Ana María Cabanillas3,*, Elisa Bal de Kier Joffé1,*, Leticia Labriola4, María Giselle Peters1,*

1Universidad de Buenos Aires, Instituto de Oncología “Ángel H. Roffo”, Area Investigación, Buenos Aires, Argentina

2Universidad de Buenos Aires, CONICET, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina

3Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba and Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Córdoba, Argentina

4Biochemistry Department, Chemistry Institute, University of São Paulo, São Paulo, Brazil

*Member of the National Council of Scientific and Technical Research (CONICET)

Correspondence to:

María Giselle Peters, email: mpeters@fmed.uba.ar, mgpeters@hotmail.com

Keywords: breast cancer, glypican-3, epithelial-mesenchymal transition, invasion, metastasis

Received: September 18, 2015    Accepted: July 16, 2016    Published: August 06, 2016

ABSTRACT

Breast cancer is the disease with the highest impact on global health, being metastasis the main cause of death. To metastasize, carcinoma cells must reactivate a latent program called epithelial-mesenchymal transition (EMT), through which epithelial cancer cells acquire mesenchymal-like traits.

Glypican-3 (GPC3), a proteoglycan involved in the regulation of proliferation and survival, has been associated with cancer. In this study we observed that the expression of GPC3 is opposite to the invasive/metastatic ability of Hs578T, MDA-MB231, ZR-75-1 and MCF-7 human breast cancer cell lines. GPC3 silencing activated growth, cell death resistance, migration, and invasive/metastatic capacity of MCF-7 cancer cells, while GPC3 overexpression inhibited these properties in MDA-MB231 tumor cell line. Moreover, silencing of GPC3 deepened the MCF-7 breast cancer cells mesenchymal characteristics, decreasing the expression of the epithelial marker E-Cadherin. On the other side, GPC3 overexpression induced the mesenchymal-epithelial transition (MET) of MDA-MB231 breast cancer cells, which re-expressed E-Cadherin and reduced the expression of vimentin and N-Cadherin. While GPC3 inhibited the canonical Wnt/β-Catenin pathway in the breast cancer cells, this inhibition did not have effect on E-Cadherin expression. We demonstrated that the transcriptional repressor of E-Cadherin - ZEB1 - is upregulated in GPC3 silenced MCF-7 cells, while it is downregulated when GPC3 was overexpressed in MDA-MB231 cells. We presented experimental evidences showing that GPC3 induces the E-Cadherin re-expression in MDA-MB231 cells through the downregulation of ZEB1.

Our data indicate that GPC3 is an important regulator of EMT in breast cancer, and a potential target for procedures against breast cancer metastasis.


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