title: 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.
authors.affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.
authors.forename: Lingmei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.
authors.forename: Lisha
authors.initials: L
authors.lastname: Qi
authors.affiliation: Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.
authors.forename: Wangzhao
authors.initials: W
authors.lastname: Song
authors.affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.
authors.forename: Yanxue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.
authors.forename: Yalei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.
authors.forename: Baocun
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Cao
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D066246:ErbB Receptors / Q000096:biosynthesis / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism*; D006923:Hymecromone / Q000494:pharmacology; D008175:Lung Neoplasms / Q000473:pathology; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D006923:Hymecromone; D004815:Epidermal Growth Factor; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C523794:HAS1 protein, human; C101754:HAS2 protein, human; C105458:HAS3 protein, human; D000076002:Hyaluronan Synthases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases