Identification of integrin α3 as a molecular marker of cells undergoing epithelial–mesenchymal transition and of cancer cells with aggressive phenotypes

Abstract

Epithelial-mesenchymal transition (EMT) is a crucial event in wound healing, tissue repair, and cancer progression in adult tissues. Transforming growth factor (TGF)-b induces EMT in mouse epithelial cells. During prolonged treatment, TGF-b successively induces myofibroblastic differentiation with increased expression of myofibroblast marker proteins, including smooth muscle a actin and calponin. We recently showed that fibroblast growth factor-2 prevented myofibroblastic differentiation induced by TGF-b, and transdifferentiated the cells to those with much more aggressive characteristics (enhanced EMT). To identify the molecular markers specifically expressed in cells undergoing enhanced EMT induced by the combination of TGF-b and fibroblast growth factor-2, we carried out a microarray-based analysis and found that integrin a3 (ITGA3) and Ret were upregulated. Intriguingly, ITGA3 was also overexpressed in breast cancer cells with aggressive phenotypes and its expression was correlated with that of dEF-1, a key regulator of EMT. Moreover, the expression of both genes was downregulated by U0126, a MEK 1 ⁄ 2 inhibitor. Therefore, ITGA3 is a potential marker protein for cells undergoing enhanced EMT and for cancer cells with aggressive phenotypes, which is positively regulated by dEF-1 and the MEK-ERK pathway. (Cancer Sci 2013; 104: 1189-1197 E pithelial-mesenchymal transition (EMT) serves as a switch directing polarized epithelial cells to transdifferentiate into mesenchymal cells. During the processes of embryonic development, wound healing, and reorganization of adult tissues, epithelial cells have been shown to lose their epithelial polarity and acquire mesenchymal phenotypes.(1) Furthermore, EMT is involved in the process of tumor-cell invasion, which also includes the loss of cell-cell interaction. Thus far, in most cases, EMT appears to be regulated by ECM components and soluble growth factors or cytokines. Of these, transforming growth factor-b (TGF-b) is considered to be the key inducer of EMT during physiological processes.(2) TGF-b is frequently and abundantly expressed in various tumors, and also induces EMT in cancer cells during cancer progression. Several extracellular signaling molecules, including Wnt, epidermal growth factor, fibroblast growth factor (FGF)-2, and tumor necrosis factor-a, cooperate with TGF-b to promote tumor invasion and metastasis as well as EMT. In addition, constitutively active Ras dramatically enhances TGF-binduced expression of Snail, a key mediator of EMT, whereas representative target genes of TGF-b are either unaffected or slightly inhibited by Ras signaling, leading to selective synergism between TGF-b and Ras as well as soluble factors in cancer progression. TGF-b has been found to induce EMT in normal mouse mammary epithelial NMuMG cells, and we recently showed that prolonged treatment of NMuMG cells with TGF-b induces the epithelial-myofibroblastic transition (EMyoT) with the expression of myofibroblast markers, smooth muscle a actin (a-SMA), and calponin.(4) During T...

Epithelial–mesenchymal transition is regulated at post‐transcriptional levels by transforming growth factor‐β signaling during tumor progression

“…ESRPs are also expressed at low levels in the basal‐like subtype, and repressed by direct binding of δEF1/SIP1 to their promoter regions, similar to the repression of E‐cadherin by δEF1/SIP1. Recently, we found that ITGA3 was highly expressed in the basal‐like subtype, and that ERK inhibitor downregulated expression of ITGA3 . When ITGA3 is functionally blocked by neutralizing antibodies or its expression is reduced by ERK inhibitor or its specific siRNA, invasive properties are significantly repressed in breast cancer cells and glioma cells .…”

Inhibition of Transforming Growth Factor‐β (TGF‐β) Signaling by Scutellaria baicalensis and Fritillaria cirrhosa Extracts in Endometrial Cancer

“…Integrins act as transmembrane scaffolds that connect the ECM to the actin cytoskeletal system; they also function as mediators of mechanotransduction and regulate cell proliferation, migration, invasion, and survival [Desgrosellier and Cheresh, ]. Upregulation of β3 integrin in response to TGF‐β is critical for initiation of the EMT process [Parvani et al, ; Shirakihara et al, ].…”

ETS1 is coexpressed with ZEB2 and mediates ZEB2‐induced epithelial‐mesenchymal transition in human tumors

“…The protein expression of E‐cadherin increased 2.3‐fold ( P < 0.05) in ZEB2‐induced shETS1‐DLD1 cells compared to shpLKO.1‐DLD1 cells (Figure B). A previous report showed that SNAIL1 expression in DLD1 cells resulted in the acquisition of invasive properties along with apparent repression of E‐cadherin but without an increase in the expression of N‐cadherin, fibronectin, and vimentin . In line with this, we could not detect vimentin expression in ZEB2‐induced DLD1 cells, and we explored the downregulation of the EMT regulator SNAIL1 and a mesenchymal marker integrin α3 in response to ETS1 knockdown in these cells .…”