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

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.

Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition

“…Patients with HCC expressing high levels of GPC3 had a shorter survival time than those expressing lower levels of this molecule. Overexpression of GPC3 enhanced epithelial markers and down-regulates vimentin and N-cadherin, indicating the potential of GPC3 to induce MET in MDA-MB231 breast cancer cells (Castillo et al, 2016). However, GPC3 can instead reduce the EMT ability of breast carcinomas.…”

“…A recent study showed a direct correlation between elevated levels of GPC3 and the expression of the EMT-associated proteins in samples from patients with hepatocellular carcinoma (HCC) (Wu et al, 2015). The silencing of GPC3 in many mouse and human breast cancer cells lines activates EMT, with increased cell migration and metastatic potential (Castillo et al, 2016). In vitro analysis revealed that GPC3 can trigger ERK-associated signaling pathways and EMT with increased cell migration and invasion contributing to the progression and metastasis of HCC (Wu et al, 2015).…”

“…The silencing of GPC3 in many mouse and human breast cancer cells lines activates EMT, with increased cell migration and metastatic potential (Castillo et al, 2016). Overexpression of GPC3 enhanced epithelial markers and down-regulates vimentin and N-cadherin, indicating the potential of GPC3 to induce MET in MDA-MB231 breast cancer cells (Castillo et al, 2016). Similar to GPC3, Glypican-5 (GPC5) is another member of the heparan sulfate proteoglycans that plays a role in tumorigenesis.…”

The significance of glypican‐3 expression profiling in the tumor cellular origin theoretical system for hepatocellular carcinoma progression

“…Glypican‐3 is expressed in progenitor cells and fetal liver, as well as in other tissues, such as pancreatic ductal adenocarcinoma and breast cancer . It plays a role in the regulation of cellular apoptosis and proliferation .…”

MEK inhibitor, PD98059, promotes breast cancer cell migration by inducing β-catenin nuclear accumulation

“…Breast cancer is one of the leading causes of cancer-related deaths in women (1). Despite the great advance in the treatment of breast cancer, the prognosis of these patients still remains poor to date (2,3). Abnormal activation of the RAF/MEK/ ERK signaling pathway has been observed in breast cancer and was proposed as a candidate for cancer therapy (4,5).…”