Major finding: The miR-200 family plays a key role in promoting metastatic colonization.
Mechanism: miR-200s target Sec23a-dependent secretion of metastatic suppressors.
Impact: The miR-200s and the tumor cell secretome may represent novel therapeutic targets.
In the early stages of metastasis, tumor cells undergo epithelial-to-mesenchymal transition (EMT), a process that is marked by loss of cell-cell adhesion and increased cell mobility. The reverse process, mesenchymal-to-epithelial transition (MET), characterizes the colonization of distant sites at which cancer cells regain epithelial properties. Recent studies have shown that expression of the adhesion molecule E-cadherin is regulated by the 5 miRNAs of the miR-200 family, which directly target repressors of E-cadherin transcription and inhibit EMT. It has therefore been hypothesized that the miR-200s are suppressors of metastasis. However, Korpal and colleagues now demonstrate that the miR-200s actually play a critical role in the completion of metastasis, specifically during metastatic colonization. The group found greater expression of miR-200s in metastatic versus nonmetastatic cells and that ectopic expression of the family enhanced colonization capacity. Further analysis identified Sec23a as a direct target of the miR-200s. Sec23a, a member of the COPII complex that mediates vesicle budding from the endoplasmic reticulum (ER), is involved in protein trafficking between the ER and the Golgi apparatus. Both loss of Sec23a and overexpression of the miR-200s led to a global reduction in protein secretion, suggesting that the miR-200s influenced the tumor cell secretome. Two members of the tumor cell secretome that act as metastatic suppressors, Tinagl1 and Igfbp4, were specifically targeted. Therefore, the data suggest that the miR-200s are dynamic players in the metastatic process; via targeting of both E-cadherin and the tumor cell secretome, the miR-200s inhibit local invasion while promoting metastatic colonization. The linkage of metastasis to the tumor secretome provides mechanistic insight into MET that may inform novel therapeutic targets.
Korpal M, Ell BJ, Buffa FM, Ibrahim T, Blanco MA, Celià-Terrassa T, et al. Direct targeting of Sec23a by MiR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med. 2011 Aug 7. [Epub ahead of print]
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