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

Li L, Qi L, Liang Z, Song W, Liu Y, Wang Y, Sun B, Zhang B, Cao W - Int. J. Mol. Med. (2015)

Bottom Line: 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 conclusion, our data demonstrate that TGF-β1 induces EMT by the transactivation of EGF signaling through HA/CD44 in lung and breast cancer cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.

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.

No MeSH data available.


Related in: MedlinePlus

Transforming growth factor-β1 (TGF-β1) is an important inducer of cell migration/invasion compared with epidermal growth factor (EGF). Transwell migration assay revealed the migratory/invasive ability of the cells following stimulation with TGF-β1 (5 ng/ml) or EGF (10 ng/ml). The graphs represent the means ± SD of 3 independent experiments. The y-axis represents the fold change in the number of cells. *P<0.05 vs. control.
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f2-ijmm-36-01-0113: Transforming growth factor-β1 (TGF-β1) is an important inducer of cell migration/invasion compared with epidermal growth factor (EGF). Transwell migration assay revealed the migratory/invasive ability of the cells following stimulation with TGF-β1 (5 ng/ml) or EGF (10 ng/ml). The graphs represent the means ± SD of 3 independent experiments. The y-axis represents the fold change in the number of cells. *P<0.05 vs. control.

Mentions: The transition between epithelial and mesenchymal cell phenotypes is not only characterized by the expression of EMT markers, but also the biological-functional and behavioral phenotypes (15). As expected, a larger number of both A549 and MCF-7 cells acquired migration and invasion ability following stimulation with TGF-β1 or EGF than the untreated control cells (Fig. 2), suggesting that stimulation with TGF-β1 and EGF led to an enhanced migratory and invasive potential of the cancer cells. In addition, a larger number of migrated/invaded cells was observed following stimulation with TGF-β1 than following stimulation with EGF. Taken together, these findings demonstrated that TGF-β1 induced EMT to a greater extent when compared with EGF. It was also suggested that TGF-β1 transactivates EGF signaling by activating EGFR.


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

Li L, Qi L, Liang Z, Song W, Liu Y, Wang Y, Sun B, Zhang B, Cao W - Int. J. Mol. Med. (2015)

Transforming growth factor-β1 (TGF-β1) is an important inducer of cell migration/invasion compared with epidermal growth factor (EGF). Transwell migration assay revealed the migratory/invasive ability of the cells following stimulation with TGF-β1 (5 ng/ml) or EGF (10 ng/ml). The graphs represent the means ± SD of 3 independent experiments. The y-axis represents the fold change in the number of cells. *P<0.05 vs. control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494581&req=5

f2-ijmm-36-01-0113: Transforming growth factor-β1 (TGF-β1) is an important inducer of cell migration/invasion compared with epidermal growth factor (EGF). Transwell migration assay revealed the migratory/invasive ability of the cells following stimulation with TGF-β1 (5 ng/ml) or EGF (10 ng/ml). The graphs represent the means ± SD of 3 independent experiments. The y-axis represents the fold change in the number of cells. *P<0.05 vs. control.
Mentions: The transition between epithelial and mesenchymal cell phenotypes is not only characterized by the expression of EMT markers, but also the biological-functional and behavioral phenotypes (15). As expected, a larger number of both A549 and MCF-7 cells acquired migration and invasion ability following stimulation with TGF-β1 or EGF than the untreated control cells (Fig. 2), suggesting that stimulation with TGF-β1 and EGF led to an enhanced migratory and invasive potential of the cancer cells. In addition, a larger number of migrated/invaded cells was observed following stimulation with TGF-β1 than following stimulation with EGF. Taken together, these findings demonstrated that TGF-β1 induced EMT to a greater extent when compared with EGF. It was also suggested that TGF-β1 transactivates EGF signaling by activating EGFR.

Bottom Line: 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 conclusion, our data demonstrate that TGF-β1 induces EMT by the transactivation of EGF signaling through HA/CD44 in lung and breast cancer cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.

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.

No MeSH data available.


Related in: MedlinePlus