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• W2077617961 abstract "Transitions between epithelial and mesenchmal phenotypes play critical roles in normal development and cancer progression. In this issue of Cancer Cell, Evdokimova et al. demonstrate that YB-1 regulates epithelial-mesenchyme transition (EMT) by inducing cap-independent translation of mRNAs encoding EMT-promoting factors and suppressing cap-dependent translation of mRNAs encoding growth-promoting factors. Transitions between epithelial and mesenchmal phenotypes play critical roles in normal development and cancer progression. In this issue of Cancer Cell, Evdokimova et al. demonstrate that YB-1 regulates epithelial-mesenchyme transition (EMT) by inducing cap-independent translation of mRNAs encoding EMT-promoting factors and suppressing cap-dependent translation of mRNAs encoding growth-promoting factors. Metastasis is a multistep process that mediates the spread of cancer cells from primary tumors to distant sites. This process relies on structural and phenotypic changes that enable tumor cells to dissociate from the tumor mass, invade the surrounding tissue, intravasate into vascular or lymphatic vessels, and extravasate and proliferate at a secondary site. An increasing number of reports provide evidence that epithelial cancer cells adopt embryonic transcription programs during the invasive phase of metastasis, which allow them to suspend some or all of their epithelial properties and acquire those of mesenchymal cells (Thiery and Sleeman, 2006Thiery J.P. Sleeman J.P. Nat. Rev. Mol. Cell Biol. 2006; 7: 131-142Crossref PubMed Scopus (3059) Google Scholar, Yilmaz and Christofori, 2009Yilmaz M. Christofori G. Cancer Metastasis Rev. 2009; 28: 15-33Crossref PubMed Scopus (1199) Google Scholar). This epithelial-to-mesenchymal transition (EMT) is associated with changes in cell-cell adhesion, remodeling of cell-matrix adhesion, and enhanced migratory activity. Several transcription factors have been implicated in this transition, including Snail, Slug, Zeb1, and Twist. The canonical Ras pathway has also been shown to play a crucial role in EMT in certain contexts. Ras activity, however, is not sufficient to induce EMT; other factors collaborate with Ras to orchestrate this process (Thiery, 2003Thiery J.P. Curr. Opin. Cell Biol. 2003; 15: 740-746Crossref PubMed Scopus (1387) Google Scholar). The relevance of EMT as an integral and obligate phase of cancer cell invasion/metastasis in vivo is controversial; in fact, several cancer cell types are able to invade by adopting modes of migration that don't involve an EMT, such as collective or amoeboid (Friedl et al., 2004Friedl P. Hegerfeldt Y. Tusch M. Int. J. Dev. Biol. 2004; 48: 441-449Crossref PubMed Scopus (310) Google Scholar). Nevertheless, an increasing body of evidence demonstrates the occurrence of EMT in tumor cell subpopulations during the progression of certain types of cancers (Yilmaz and Christofori, 2009Yilmaz M. Christofori G. Cancer Metastasis Rev. 2009; 28: 15-33Crossref PubMed Scopus (1199) Google Scholar, Polyak and Weinberg, 2009Polyak K. Weinberg R.A. Nature Rev. Cancer. 2009; 9: 265-273Crossref PubMed Scopus (2463) Google Scholar), and a recent study shows that EMT in vivo might be particularly important for a subset of tumors, especially for those with basal phenotype (Sarrio et al., 2008Sarrio D. Rodriguez-Pinilla S.M. Hardisson D. Cano A. Moreno-Bueno G. Palacios J. Cancer Res. 2008; 68: 989-997Crossref PubMed Scopus (793) Google Scholar). In this issue of Cancer Cell, Evdokimova, Sorensen, and colleagues identify YB-1 (Y-box binding protein-1) as a new player in the regulation of EMT through a novel mechanism involving translation of cap-independent mRNAs encoding Snail and other EMT regulators in Ras-transformed cells (Evdokimova et al., 2009Evdokimova V. Tognon C. Ng T. Ruzanov P. Melnyk N. Fink D. Sorokin A. Ovchinnikov L.P. Davicioni E. Triche T.J. et al.Cancer Cell. 2009; 15 (this issue): 402-415Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar). YB-1, a DNA/RNA-binding protein with a conserved cold-shock domain, has been implicated in tumor progression; however, the exact role of YB-1 in this process is ambiguous since it has been described as both a tumor suppressor and an oncogene. YB-1's activity as a transcriptional activator in the nucleus has been reported to be protumorigenic: YB-1 induces proliferation by activating progrowth genes through binding to the Y-box elements in their promoter region (Evdokimova et al., 2006Evdokimova V. Ovchinnikov L.P. Sorensen P.H. Cell Cycle. 2006; 5: 1143-1147Crossref PubMed Scopus (91) Google Scholar). In contrast, in the cytoplasm, YB-1 can silence translation through binding to the 5′ terminus of mRNAs with extensive 5′ UTR secondary structures, thus outcompeting the eIF4E initiation complex (Evdokimova et al., 2006Evdokimova V. Ovchinnikov L.P. Sorensen P.H. Cell Cycle. 2006; 5: 1143-1147Crossref PubMed Scopus (91) Google Scholar). Many of these YB-1-silenced mRNAs encode growth-related proteins and are dependent on 5′ cap-binding proteins for initiation of translation. Hence, YB-1 can suppress growth and proliferation and has been described to possess tumor suppressor properties (Evdokimova et al., 2006Evdokimova V. Ovchinnikov L.P. Sorensen P.H. Cell Cycle. 2006; 5: 1143-1147Crossref PubMed Scopus (91) Google Scholar). In this issue's report, YB-1 is described as a crucial factor in the initiation of the translation of a set of cap-independent mRNA transcripts. Microarray analysis of translationally active and inactive mRNAs identified several known EMT-regulatory factors, including the transcription factors Snail1 and Twist, that were differentially translated in Ras-transformed cells. The authors further demonstrated that YB-1 overexpression could increase Snail1 protein expression and induce subsequent EMT. The 5′ UTR of Snail1 mRNA is predicted to form highly stable stem-loop structures with conserved nucleotides, resembling the structure of internal ribosome entry sites (IRES), which mediate cap-independent translation initiation directly activated by YB-1 binding. In parallel, YB-1 overexpression in Ras-transformed human breast epithelial cells suppressed translation of transcripts involved in cell proliferation and induced proliferation arrest. Hence, YB-1 plays a dichotomous role in translational regulation: it suppresses the cap-dependent translation initiation of progrowth mRNAs and promotes the cap-independent translation initiation of EMT-inducing mRNAs, the transcription of which is induced by sustained Ras-Erk activation. Therefore, EMT induction in Ras-transformed cells involves two steps: (1) Ras induces the transcription of EMT-mediating factors (including Snail 1 and Twist) and (2) YB-1 induces the translation of these factors concomitant with the suppression of the expression of growth related transcripts (Figure 1). While the studies in this report involved analysis of tumor cells expressing an H-Ras oncogene, it is predicted that YB-1 could collaborate with other genes that promote transcription of EMT-regulatory mRNAs. These studies highlight the critical role of YB-1 in the coordinated induction of both EMT and proliferation arrest. Interestingly, an invasion “signature,” derived by analysis of mRNAs from invading cells associated with mouse and rat tumors, exhibited an increase in the expression levels of genes that induce migration and suppress proliferation and apoptosis and a decrease in the expression levels of genes that promote proliferation (Condeelis et al., 2005Condeelis J. Singer R.H. Segall J.E. Annu. Rev. Cell Dev. Biol. 2005; 21: 695-718Crossref PubMed Scopus (271) Google Scholar); this change in gene expression is consistent with a coordination of invasive behavior and proliferation arrest. The dormancy of invading cells, moreover, could contribute to the failure of most tumor cells to expand at secondary sites. YB-1 expression could arrest proliferation of metastatic cells through silencing of translation of mRNAs required for proliferation. If such a mechanism takes place, release from dormancy may involve inactivation of YB-1 translational regulation. Akt phosphorylation of YB-1 has been shown to inhibit YB-1 binding to the 5′UTR cap (Evdokimova et al., 2006Evdokimova V. Ovchinnikov L.P. Sorensen P.H. Cell Cycle. 2006; 5: 1143-1147Crossref PubMed Scopus (91) Google Scholar). Thus, this phosphorylation event is predicted to promote proliferation by releasing the YB-1 imposed block on the translation of growth-regulatory genes. Interestingly, it has been suggested that the escape from dormancy at metastatic sites is contingent on the reversal of EMT in a mesenchymal-to-epithelial transition (MET) (Chaffer et al., 2007Chaffer C.L. Thompson E.W. Williams E.D. Cells Tissues Organs. 2007; 185: 7-19Crossref PubMed Scopus (235) Google Scholar, Polyak and Weinberg, 2009Polyak K. Weinberg R.A. Nature Rev. Cancer. 2009; 9: 265-273Crossref PubMed Scopus (2463) Google Scholar). Another interesting finding in this report is that YB-1 regulates expression of several progenitor cell markers (upregulation of p63, CD44, and CD10, and downregulation of CD24). This is consistent with recent studies that indicate a link between EMT and acquisition of stem/progenitor cell properties (Polyak and Weinberg, 2009Polyak K. Weinberg R.A. Nature Rev. Cancer. 2009; 9: 265-273Crossref PubMed Scopus (2463) Google Scholar). Together, these studies support the notion that tumor cells undergo dedifferentiation through EMT. During metastatic progression, this dedifferentiated mesenchymal state could revert back to an epithelial state (MET) upon expansion at secondary tumor sites. According to this scenario, cancer cells that metastasize could be derived from primary site epithelial tumor cells that underwent a transient dedifferentiation associated with EMT rather than cancer stem cells that pre-exist as a subpopulation of the primary tumor. YB-1 gain or loss of translational control could potentially be involved in the regulation of both EMT and MET, respectively. These studies raise the question: is YB-1 a target for therapeutic intervention in metastasis? As the authors point out, direct targeting of YB-1 might prove to be futile or even counterproductive since YB-1 could be an important factor in keeping cells dormant after they metastasize." @default.
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• W2077617961 title "YB-1 Translational Control of Epithelial-Mesenchyme Transition" @default.
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