| Epithelial-to-mesenchymal transition (EMT) is a physiologic process in whichcells lose epithelial characteristics, such as cell-to-cell contact, and acquiremesenchymal morphological phenotype, such as increased cell motility. It has beenreported that EMT plays important roles in embryo development and organdifferentiation. Besides its involvement in embryonic implantation and gastrulation,wound healing and tissue-regeneration and organ fbrosis, EMT is also considered asone of the important mechanisms regulating the progression of variable solid tumors,especially the invasive behavior of cancer cells.Moreover, EMT is involved in tumormetastasis.Transcription factor FOXM1is one of the Forkhead box family menbers and isoverexpressed in various human malignancies including breast cancer and lung cancer.FOXM1plays a key role in tumor development and progression. Thus, FOXM1isconsidered as a potential target gene for tumorigenesis prevention and anti-cancertherapy.In this study, we investigated the function of FOXM1in EMT process of lungcancer and breast cancer cells. The main results were listed as follow ed:(1) We measured the mRNA and protein levels of FOXM1in epithelial-type breastcancer cell lines MCF-7s and mesenchymal-type breast cancer cell line MDA-MB-231. It was found that the expression levels of FOXM1were associated withepithelial/mesenchymal characteristics and migration ability of cells. The similarresults were observed in epithelial and mesenchymal lung cancer cell lines.Furthermore，the expression levels of FOXM1and Vimentin were detected in theclinical samples of patients with lung cancer. We found that the expression levels ofFOXM1were higher in patient samples with metastasis than that in non-metastasissamples, while the expression levels of Vimentin in the two groups were accordant.(2) In the EMT process of TGF-β induced A549，the migration ability of cellswere enforced and the FOXM1expression were gradually elevated. Furthermore,down-regulated FOXM1inhibits the migration of the cells during TGF-β-induced EMTprocess, and the expression of mesenchymal marker Vimentin was decreased. Theseresults suggested that FOXM1could maintain the epithelial phenotype of the tumorcells and promote the cell migration. (3) In order to confirm the relation between FOXM1and tumor EMT, we usedFOXM1specific siRNA to repress the expression of FOXM1in MDA-MB-231cells.The knockdown of FOXM1dramatically decreased the cell migration ofMDA-MB-231cells, increased mRNA expression of epithelial-related E-cadherin anddecreased mRNA expression of mesenchymal-related Vimentin, Slug, Snail, and Twist.On the other hand, we infected MCF-7cells with a lentiviral vector expressingFOXM1and selected the MCF-7cell clones stably expressing FOXM1. A series ofexperiments were performed and demonstrated that FOXM1-expressing MCF-7cellclones showed the mesenchymal phenotype. All these results indicated that FOXM1was required for maintaining the mesenchymal characteristic of breast cancer cells andwas able to induce EMT of epithelial breast cancer cells.(4) The similar experments were performed in lung cancer cell line A549andH1229. And the same results were found as breast cancer.(5) The Chip and co-transfect assay suggested that the Slug gene was one of thedirect transcriptional targets of FOXM1in breast cancer cells. To further confirmwhether the EMT induced by FOXM1overexpression in MCF-7cells was mediated bySlug， we used a Slug specific siRNA to inhibit the expression of Slug inFOXM1-expressing MCF-7clone cells and found that the cells behave thecharacteristic of epithelial cells.Together, these results suggested that the EMTinduced by FOXM1in breast cancer cells was mediated by Slug.(6) We also found that the downstream target gene of FOXM1was Twist in lungcancer cells by A series of experiments. Knockdown of Twist could inhibit the effectof FOXM1induced EMT in lung cancer, these results showed that Twist was the keyfactor of FOXM1induced EMT in lung cancer.(7) To determine the effect of FOXM1on metastasis of breast cancer cells in vivo,we generated metastasis models in nude mice through the tail vein injection and foundthat FOXM1promoted metastasis of breast cancer cells in vivo. |
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