Targets of the Tumor Suppressor miR-200 in Regulation of the Epithelial-Mesenchymal Transition in Cancer

Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Cancer Research (Impact Factor: 9.33). 12/2011; 71(24):7670-82. DOI: 10.1158/0008-5472.CAN-11-0964
Source: PubMed


The microRNA-200 (miR-200) family restricts epithelial-mesenchymal transition (EMT) and metastasis in tumor cell lines derived from mice that develop metastatic lung adenocarcinoma. To determine the mechanisms responsible for EMT and metastasis regulated by this microRNA, we conducted a global liquid chromatography/tandem mass spectrometry analysis to compare metastatic and nonmetastatic murine lung adenocarcinoma cells which had undergone EMT because of loss of miR-200. An analysis of syngeneic tumors generated by these cells identified multiple novel proteins linked to metastasis. In particular, the analysis of conditioned media, cell surface proteins, and whole-cell lysates from metastatic and nonmetastatic cells revealed large-scale modifications in the tumor microenvironment. Specific increases were documented in extracellular matrix (ECM) proteins, peptidases, and changes in distribution of cell adhesion proteins in the metastatic cell lines. Integrating proteomic data from three subproteomes, we defined constituents of a multilayer protein network that both regulated and mediated the effects of TGFβ. Lastly, we identified ECM proteins and peptidases that were directly regulated by miR-200. Taken together, our results reveal how expression of miR-200 alters the tumor microenvironment to inhibit the processes of EMT and metastasis.

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    • "Initial formation of pro-metastatic cells predisposed to successful accomplishment of metastatic cascade is commonly associated with epithelial–mesenchymal transition (EMT)— a morphological transformation necessary for escape from the primary tumor and subsequent invasion and metastatic growth. As discussed above, the mir-200c family is a well-known regulator of this mechanism through targeting of the TGF-beta pathway [66–69]. Upstream modulators of ZEB1 and mir-200c expression such as WASF3 and OSM have also been identified to play a role in EMT progression and tumor metastases [70, 71]. "
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    • "In ovarian and breast cancer, low expression of miRNA-200 plays important roles in cancer metastasis [14,17,18]. MiR-200 changed the tumor environment, inhibiting the process of EMT and metastasis [19,20]. These findings hypothesizes that the expression of miR-200 in pancreatic cancer cell is correlated with stemness, EMT and metastasis. "
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    • "Mouse models support a role for these miRNAs in metastasis: miR-200 overexpression blocked the capacity of metastasis-prone tumor cells to undergo EMT and reduced the metastatic potential of these cells [101]. miRNA profiling of lung cancer cells has also suggested a role for these miRNAs in the regulation of EMT and invasion, indicating that multiple peptidases, cell adhesion proteins, extracellular matrix proteins, and cytoskeletal regulators are regulated by miR-200 [102]. "
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