Transforming growth factor-β1 induces EMT by the transactivation of epidermal growth factor signaling through HA/CD44 in lung and breast cancer cells

Abstract

Epithelial-mesenchymal transition (EMT), a process closely related to tumor development, is regulated by a variety of signaling pathways and growth factors, such as transforming growth factor-β1 (TGF-β1) and epidermal growth factor (EGF). Hyaluronan (HA) has been shown to induce EMT through either TGF-β1 or EGF signaling and to be a regulator of the crosstalk between these two pathways in fibroblasts. In this study, in order to clarify whether HA has the same effect in tumor cells, we utilized the lung cancer cell line, A549, and the breast cancer cell line, MCF-7, and found that the effects of stimulation with TGF-β1 were more potent than those of EGF in regulating the expression of EMT-associated proteins and in enhancing cell migration and invasion. In addition, we observed that TGF-β1 activated EGF receptor (EGFR) and its downstream AKT and extracellular signal-regulated kinase (ERK) pathways. Furthermore, we found that TGF-β1 upregulated the expression of hyaluronan synthases (HAS1, HAS2 and HAS3) and promoted the expression of CD44, a cell surface receptor for HA, which interacts with EGFR, resulting in the activation of the downstream AKT and ERK pathways. Conversely, treatment with 4-methylumbelliferone (4-MU; an inhibitor of HAS) prior to stimulation with TGF-β1, inhibited the expression of CD44 and EGFR, abolished the interaction between CD44 and EGFR. Furthermore, the use of shRNA targeting CD44 impaired the expression of EGFR, deactivated the AKT and ERK pathways, reversed EMT and decreased the migration and invasion ability of cells. In conclusion, our data demonstrate that TGF-β1 induces EMT by the transactivation of EGF signaling through HA/CD44 in lung and breast cancer cells.

A FASN-TGF-β1-FASN regulatory loop contributes to high EMT/metastatic potential of cisplatin-resistant non-small cell lung cancer

“…The TGF-β1-induced EMT and increased invasion in various types of cancers has previously been suggested [36]. In this study, we found a FASN-TGFβ1-FASN positive feedback loop in cisplatin-resistant lung cancer cells, but not in parental cells.…”

Targeting highly expressed extracellular HSP90 in breast cancer stem cells inhibits tumor growthin vitroandin vivo

“…Such examples are the Notch receptors, 43 the insulin-like growth factor I receptor 44 and the CD44 receptor, which is also an established marker for BCSC. 45 Interestingly, and although EGFR overexpression is associated with breast cancer cell proliferation and invasion, 46 Kari et al 47 reported that malignant tumor cells faced with inadequate cell-matrix contacts, critically depend on EGFR activation for survival. Taking into account that mAb4C5 significantly inhibits the growth of MDA-MB-231 and mammosphere tumors, we next examined the possible therapeutic effect of this antibody on palpable tumors derived from mammospheres, taking into consideration that this subpopulation is greatly enriched in cells with the CD44 C /CD24 ¡/ low BCSC phenotype and additionally over-expresses eHSP90.…”

Honokiol inhibits EMT-mediated motility and migration of human non-small cell lung cancer cells in vitro by targeting c-FLIP

“…EMT is involved in various functions and leads to the dissociation of cell-cell adhesions, disappearance of apical-basolateral polarity, reorganization of spindle-cell shape, promotion of cell motility, and acquisition of mesenchymal markers [2] . It is well known that transforming growth factor-β (TGF-β) is a major inducer of EMT in cancer cells during tumor progression [3] . Tumor necrosis factor-α (TNF-α) is able to accelerate the EMT process induced by TGF-β [4] .…”