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MicroRNA-7 inhibits tumor metastasis and reverses epithelial-mesenchymal transition through AKT/ERK1/2 inactivation by targeting EGFR in epithelial ovarian cancer.

Zhou X, Hu Y, Dai L, Wang Y, Zhou J, Wang W, Di W, Qiu L - PLoS ONE (2014)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China.

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.

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miR-7 and EGFR are inersely expressed in EOC tissues.(A) Expression of miR-7 in primary EOC and its matched metastatic tissue by CISH. (B) Expression of EGFR in primary EOC and its matched metastatic tissue by IHC. (*P<0.05. **P<0.01).
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pone-0096718-g008: miR-7 and EGFR are inersely expressed in EOC tissues.(A) Expression of miR-7 in primary EOC and its matched metastatic tissue by CISH. (B) Expression of EGFR in primary EOC and its matched metastatic tissue by IHC. (*P<0.05. **P<0.01).

Mentions: We used CISH and IHC to detect the expression of miR-7 and EGFR in the same type of tissue. We determined whether miR-7 expression was associated with EGFR expression in EOC tissuses. The tissue contained 25 pairs of primary EOC tissues and their matched metastatic tissues. The CISH analysis showed an overt reduction of miR-7 in the metastatic tissues compared with their corresponding primary EOC tissues (Figure 8A, Table 1). By contrast, IHC results revealed that EGFR expression was higher in metastatic tissues than in primary EOC tissues (Figure 8B, Table 2). Furthermore, statistical analysis showed that EGFR expression was inversely correlated with miR-7 expression (Table 3).


MicroRNA-7 inhibits tumor metastasis and reverses epithelial-mesenchymal transition through AKT/ERK1/2 inactivation by targeting EGFR in epithelial ovarian cancer.

Zhou X, Hu Y, Dai L, Wang Y, Zhou J, Wang W, Di W, Qiu L - PLoS ONE (2014)

miR-7 and EGFR are inersely expressed in EOC tissues.(A) Expression of miR-7 in primary EOC and its matched metastatic tissue by CISH. (B) Expression of EGFR in primary EOC and its matched metastatic tissue by IHC. (*P<0.05. **P<0.01).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4016102&req=5

pone-0096718-g008: miR-7 and EGFR are inersely expressed in EOC tissues.(A) Expression of miR-7 in primary EOC and its matched metastatic tissue by CISH. (B) Expression of EGFR in primary EOC and its matched metastatic tissue by IHC. (*P<0.05. **P<0.01).
Mentions: We used CISH and IHC to detect the expression of miR-7 and EGFR in the same type of tissue. We determined whether miR-7 expression was associated with EGFR expression in EOC tissuses. The tissue contained 25 pairs of primary EOC tissues and their matched metastatic tissues. The CISH analysis showed an overt reduction of miR-7 in the metastatic tissues compared with their corresponding primary EOC tissues (Figure 8A, Table 1). By contrast, IHC results revealed that EGFR expression was higher in metastatic tissues than in primary EOC tissues (Figure 8B, Table 2). Furthermore, statistical analysis showed that EGFR expression was inversely correlated with miR-7 expression (Table 3).

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Gynecology and Obstetrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, China.

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.

Show MeSH
Related in: MedlinePlus