Glypican-3 induces a mesenchymal to epithelial transition in human breast cancer cells
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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)
Keywords: breast cancer, glypican-3, epithelial-mesenchymal transition, invasion, metastasis
Received: September 18, 2015 Accepted: July 16, 2016 Published: August 06, 2016
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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