MiR-200 can repress breast cancer metastasis through ZEB1-independent but moesin-dependent pathways

X. Li, S. Roslan, C. N. Johnstone, J. A. Wright, C. P. Bracken, M. Anderson, A. G. Bert, L. A. Selth, R. L. Anderson, G. J. Goodall, P. A. Gregory, Y. Khew-Goodall

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85 Citations (Scopus)

Abstract

The microRNA-200 (miR-200) family has a critical role in regulating epithelial-mesenchymal transition and cancer cell invasion through inhibition of the E-cadherin transcriptional repressors ZEB1 and ZEB2. Recent studies have indicated that the miR-200 family may exert their effects at distinct stages in the metastatic process, with an overall effect of enhancing metastasis in a syngeneic mouse breast cancer model. We find in a xenograft orthotopic model of breast cancer metastasis that ectopic expression of members of the miR-200b/200c/429, but not the miR-141/200a, functional groups limits tumour cell invasion and metastasis. Despite modulation of the ZEB1-E-cadherin axis, restoration of ZEB1 in miR-200b-expressing cells was not able to alter metastatic potential suggesting that other targets contribute to this process. Instead, we found that miR-200b repressed several actin-associated genes, with the knockdown of the ezrin-radixin-moesin family member moesin alone phenocopying the repression of cell invasion by miR-200b. Moesin was verified to be directly targeted by miR-200b, and restoration of moesin in miR-200b-expressing cells was sufficient to alleviate metastatic repression. In breast cancer cell lines and patient samples, the expression of moesin significantly inversely correlated with miR-200 expression, and high levels of moesin were associated with poor relapse-free survival. These findings highlight the context-dependent effects of miR-200 in breast cancer metastasis and demonstrate the existence of a moesin-dependent pathway, distinct from the ZEB1-E-cadherin axis, through which miR-200 can regulate tumour cell plasticity and metastasis.

Original languageEnglish
Pages (from-to)4077-4088
Number of pages12
JournalOncogene
Volume33
DOIs
Publication statusPublished - 31 Jul 2014
Externally publishedYes

Keywords

  • Actin cytoskeleton
  • Breast cancer
  • Epithelial-mesenchymal transition
  • Metastasis
  • MiR-200

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    Li, X., Roslan, S., Johnstone, C. N., Wright, J. A., Bracken, C. P., Anderson, M., Bert, A. G., Selth, L. A., Anderson, R. L., Goodall, G. J., Gregory, P. A., & Khew-Goodall, Y. (2014). MiR-200 can repress breast cancer metastasis through ZEB1-independent but moesin-dependent pathways. Oncogene, 33, 4077-4088. https://doi.org/10.1038/onc.2013.370