The miR-200 family and the miR-183∼96∼182 cluster target Foxf2 to inhibit invasion and metastasis in lung cancers

Metastatic lung cancer is one of the most lethal forms of cancer and molecular pathways driving metastasis are still not clearly elucidated. Metastatic cancer cells undergo an epithelial-mesenchymal transition (EMT) where they lose their epithelial properties and acquire a migratory and invasive phenotype. Here we identify that the expression of microRNAs from the miR-200 family and the miR-183∼96∼182 cluster are significantly co-repressed in non-small cell lung cancer cell lines and primary tumors from multiple TCGA dataset with high EMT scores. Ectopic expression of the miR-183∼96∼182 cluster inhibited cancer cell migration and invasion, whereas its expression was tightly modulated by miR-200. We identified Foxf2 as a common, novel and direct target of both these microRNA families. Foxf2 expression tightly correlates with the transcription factor Zeb1 and is elevated in mesenchymal-like metastatic lung cancer cells. Foxf2 expression induced robust EMT, migration, invasion and metastasis in lung cancer cells, whereas Foxf2 inhibition significantly repressed these phenotypes. We also demonstrated that Foxf2 transcriptionally represses E-cadherin and miR-200, independent of Zeb1, to form a double-negative feedback loop. We, therefore, identified a novel mechanism whereby the miR-200 family and the miR-183∼96∼182 cluster inhibit lung cancer invasion and metastasis by targeting Foxf2.