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Transforming growth factor-?1 induces EMT by the transactivation of epidermal
growth factor signaling through HA/CD44 in lung and breast cancer cells
#MMPMID26005723
Li L
; Qi L
; Liang Z
; Song W
; Liu Y
; Wang Y
; Sun B
; Zhang B
; Cao W
Int J Mol Med
2015[Jul]; 36
(1
): 113-22
PMID26005723
show ga
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-?1 (TGF-?1) and epidermal growth factor (EGF).
Hyaluronan (HA) has been shown to induce EMT through either TGF-?1 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-?1 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-?1 activated EGF receptor (EGFR) and its downstream AKT and extracellular
signal-regulated kinase (ERK) pathways. Furthermore, we found that TGF-?1
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-?1, 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-?1 induces EMT by the
transactivation of EGF signaling through HA/CD44 in lung and breast cancer cells.
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