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

X Li, S Roslan, CN Johnstone, JA Wright, CP Bracken… - Oncogene, 2014 - nature.com
X Li, S Roslan, CN Johnstone, JA Wright, CP Bracken, M Anderson, AG Bert, LA Selth
Oncogene, 2014nature.com
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 …
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.
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