Abstract
Epidermal growth factor receptor (EGFR) overexpression and activation result in increased proliferation and migration of solid tumors including ovarian cancer. In recent years, mounting evidence indicates that EGFR is a direct and functional target of miR-7. In this study, we found that miR-7 expression was significantly downregulated in highly metastatic epithelial ovarian cancer (EOC) cell lines and metastatic tissues, whereas the expression of, EGFR correlated positively with metastasis in both EOC patients and cell lines. Overexpression of miR-7 markedly suppressed the capacities of cell invasion and migration and resulted in morphological changes from a mesenchymal phenotype to an epithelial-like phenotype in EOC. In addition, overexpression of miR-7 upregulated CK-18 and β-catenin expression and downregulated Vimentin expression, accompanied with EGFR inhibition and AKT/ERK1/2 inactivation. Similar to miR-7 transfection, silencing of EGFR with this siRNA in EOC cells also upregulated CK-18 and β-catenin expression and downregulated Vimentin expression, and decreased phosphorylation of both Akt and ERK1/2, confirming that EGFR is a target of miR-7 in reversing EMT. The pharmacological inhibition of PI3K-AKT and ERK1/2 both significantly enhanced CK-18 and β-catenin expression and suppressed vimentin expression, indicating that AKT and ERK1/2 pathways are required for miR-7 mediating EMT. Finally, the expression of miR-7 and EGFR in primary EOC with matched metastasis tissues was explored. It was showed that miR-7 is inversely correlated with EGFR. Taken together, our results suggested that miR-7 inhibited tumor metastasis and reversed EMT through AKT and ERK1/2 pathway inactivation by reducing EGFR expression in EOC cell lines. Thus, miR-7 might be a potential prognostic marker and therapeutic target for ovarian cancer metastasis intervention.
Highlights
Ovarian cancer is the major cause of deaths from gynecologic malignancies and the 5th leading cause of cancer-related deaths among women in the world [1]
We show that miR-7 reverses epithelial-mesenchymal transition (EMT) through AKT/ERK1/2 inactivation by targeting epidermal growth factor receptor (EGFR) in epithelial ovarian cancer (EOC), which provides a novel insight into the mechanisms underlying metastasis of ovarian cancer
Our results suggest that down-regulation of miR-7 is correlated with increased EOC metastasis and that miR-7 might suppress EOC progression
Summary
Ovarian cancer is the major cause of deaths from gynecologic malignancies and the 5th leading cause of cancer-related deaths among women in the world [1]. It has been speculated that metastasis remains the leading cause of relapse and death from ovarian cancer, and yet the molecular mechanisms associated with acquisition of metastatic ability in human ovarian cancer are poorly understood. A range of miRNAs have been identified that function as classical oncogenes or tumor suppressor genes [6,7,8]. MiR-7 has been characterized as a tumor suppressor in several human cancers. It targets a number of proto-oncogenes, including insulin-like growth factor-1 receptor (IGF1R) [9] epidermal growth factor receptor (EGFR) [10], p21-activated kinase 1 (Pak1) and associated cdc kinase 1 (Ack1) [11]. It9s demonstrated that overexpression of miR-7 inhibited schwannoma cell growth both in culture and in xenograft tumor models in vivo, which correlated with downregulation of EGFR, Pak and Ack1 [11]
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