MicroRNA-7 Inhibits Tumor Metastasis and Reverses Epithelial-Mesenchymal Transition through AKT/ERK1/2 Inactivation by Targeting EGFR in Epithelial Ovarian Cancer

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.

LRIG1 inhibits hypoxia-induced vasculogenic mimicry formation via suppression of the EGFR/PI3K/AKT pathway and epithelial-to-mesenchymal transition in human glioma SHG-44 cells

“…There exists precedent for modulating EMT through the suppression of EGFR. Zhou et al (2014) showed that suppression of EGFR by miRNA-7 is able to inactivate the ERK-1/2/ATK signaling cascade, thus reversing EMT and attenuating metastasis in epithelial ovarian cancer cells. Zuo et al (2011) found that EGFR activation can induce EMT-like phenotype change and MMP-9-mediated degradation of E-cadherin in HNSCC SCC10A cells through the ERK-1/2 and PI3K signaling pathways.…”

Circular RNA participates in the carcinogenesis and the malignant behavior of cancer

“…MiR-7 also suppresses the effector of EGFR signaling by inactivating protein kinase B (PKB/Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2). [43][44][45] Therefore, the regulatory function of circRNAs via their influence on miR-7 is clear: overexpression of ciRS-7 could act as a microRNA sponge to restrain the expression miR-7 and therefore elevate EGFR expression. EGFR overexpression is associated with disease advancement, resistance to chemotherapy and radiation therapy, and poor prognosis, and is closely observed in a series of solid tumors, including cancer stem-like cells (CSC), gastric cancer, hepatocellular carcinoma and colorectal carcinoma.…”

“…48 In hepatocellular carcinoma (HCC), miR-7 is decreased in HCC cell plasma and several studies have confirmed its outstanding role in cell cycle regulation. [42][43][44] MiR-7 directly silences the cyclin E1 (CCNE1) gene, and CCNE1 forms a complex with and functions as a regulatory subunit of CDK2, which is required for G1 to S transition. 49 Therefore, the overexpression of miR-7 arrests the cell cycle in HCC.…”

Role of microRNA-7 in digestive system malignancy

“…Also, miR-7 is expressed abundantly in human pancreas and endocrine cells and has a specific role in endocrine cell differentiation and function [10] . It has been demonstrated that miR-7 is a tumor suppressor in breast, lung and ovarian cancers, and glioblastoma, mainly focusing on its relationship with EGFR [11][12][13][14][15] . Accumulating evidence shows that miR-7 can simultaneously target a variety of mRNAs involved in diverse signaling pathways in different tumors.…”