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MicroRNA-493 suppresses tumor growth, invasion and metastasis of lung cancer by regulating E2F1.

Gu Y, Cheng Y, Song Y, Zhang Z, Deng M, Wang C, Zheng G, He Z - PLoS ONE (2014)

Bottom Line: Our data indicated that the expression of miR-493 was markedly reduced in pulmonary carcinoma.The ectopic expression of miR-493 impaired cell growth and invasion in vitro and in vivo.Mechanically, miR-493 commonly directly targeted E2F1, which resulted in a robust reduction of the expression of mRNA and protein.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research Institute and Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong, PR China; Medical School, University of South China, Hengyang, Hunan, PR China.

ABSTRACT
miRNAs have been proposed to be key regulators of progression and metastasis in cancer. However, an understanding of their roles and molecular mechanisms is needed to provide deeper insights for better therapeutic opportunities. In this study we investigated the role and mechanism of miR-493 in the development and progression of nonsmall-cell lung cancer (NSCLC). Our data indicated that the expression of miR-493 was markedly reduced in pulmonary carcinoma. The ectopic expression of miR-493 impaired cell growth and invasion in vitro and in vivo. Mechanically, miR-493 commonly directly targeted E2F1, which resulted in a robust reduction of the expression of mRNA and protein. This effect, in turn, decreased the growth, invasion and metastasis of lung cancer cells. Our findings highlight the importance of miR-493 dysfunction in promoting tumor progression, and implicate miR-493 as a potential therapeutic target in lung cancer.

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miR-493 inhibits the AKT and ERK pathways by targeting E2F1.(A) miR-493 overexpression reduced the activity of the AKT and ERK pathways in 95D and H1975 cells. (B) The knockdown of miR-493 by with anti-miR- 493 increased the activity of AKT and ERK signaling in HBE, A549 and H1299 cells. (C) miR-493 (or scramble control) transfection followed by E2F1 (or mock vector) transfection 24 hours later in 95D cells affects AKT and ERK signaling. The AKT pathway activity was measured by examining the expression of phosphorylated AKT (pAKT), whereas the EKR pathway activity was measured by examining expression of phosphorylated ERK (pERK).
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pone-0102602-g006: miR-493 inhibits the AKT and ERK pathways by targeting E2F1.(A) miR-493 overexpression reduced the activity of the AKT and ERK pathways in 95D and H1975 cells. (B) The knockdown of miR-493 by with anti-miR- 493 increased the activity of AKT and ERK signaling in HBE, A549 and H1299 cells. (C) miR-493 (or scramble control) transfection followed by E2F1 (or mock vector) transfection 24 hours later in 95D cells affects AKT and ERK signaling. The AKT pathway activity was measured by examining the expression of phosphorylated AKT (pAKT), whereas the EKR pathway activity was measured by examining expression of phosphorylated ERK (pERK).

Mentions: E2F1 plays a critical role in cell-cycle progression, which in turn promotes cells proliferation and metastasis. However, the precise mechanism of E2F1 function is complex and depends on cellular context [18]. A recent study indicated that E2F1-dependent tumor progression was triggered by the activation of the cytoplasmic Ras/Raf signaling cascades, such as the PI3K-AKT [16] and MEK-ERK pathways [19], most of which regulate cell proliferation, survival and invasion [20], [21]. Thus, we investigated t whether miR-493 regulates these pathways by targeting E2F1. The upregulation of miR-493, via the transfection of miR-493, in 95D and H1975 cells decreased the phosphorylation levels of AKT and its downstream target GSK3β (figure 6A). Similarly, miR-493 also suppressed the levels of phosphorylated ERK (figure 6A). We also observed that the knockdown of miR-493 via transfection with anti-miR-493 in HBE, A549 and H1299 cells, in which the relative expression level of miR-493 was higher, increased the levels of phosphorylated AKT, GSK3b and ERK (figure 6B). These western blotting results demonstrated that miR-493 is negative regulator of the AKT and ERK pathways. Subsequently, rescue experiments were performed by overexpressing the E2F1-Δ3′- UTR vector (without an endogenous 3′-UTR) in miR-493-treated cells. The miR-493-induced downregulation of E2F1 was rescued upon the introduction of E2F1 (figure 6C), and the phosphorylation levels of AKT and ERK were altered in a similar manner. These observations suggest that miR-493 inhibits the AKT and ERK pathways by targeting E2F1.


MicroRNA-493 suppresses tumor growth, invasion and metastasis of lung cancer by regulating E2F1.

Gu Y, Cheng Y, Song Y, Zhang Z, Deng M, Wang C, Zheng G, He Z - PLoS ONE (2014)

miR-493 inhibits the AKT and ERK pathways by targeting E2F1.(A) miR-493 overexpression reduced the activity of the AKT and ERK pathways in 95D and H1975 cells. (B) The knockdown of miR-493 by with anti-miR- 493 increased the activity of AKT and ERK signaling in HBE, A549 and H1299 cells. (C) miR-493 (or scramble control) transfection followed by E2F1 (or mock vector) transfection 24 hours later in 95D cells affects AKT and ERK signaling. The AKT pathway activity was measured by examining the expression of phosphorylated AKT (pAKT), whereas the EKR pathway activity was measured by examining expression of phosphorylated ERK (pERK).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126682&req=5

pone-0102602-g006: miR-493 inhibits the AKT and ERK pathways by targeting E2F1.(A) miR-493 overexpression reduced the activity of the AKT and ERK pathways in 95D and H1975 cells. (B) The knockdown of miR-493 by with anti-miR- 493 increased the activity of AKT and ERK signaling in HBE, A549 and H1299 cells. (C) miR-493 (or scramble control) transfection followed by E2F1 (or mock vector) transfection 24 hours later in 95D cells affects AKT and ERK signaling. The AKT pathway activity was measured by examining the expression of phosphorylated AKT (pAKT), whereas the EKR pathway activity was measured by examining expression of phosphorylated ERK (pERK).
Mentions: E2F1 plays a critical role in cell-cycle progression, which in turn promotes cells proliferation and metastasis. However, the precise mechanism of E2F1 function is complex and depends on cellular context [18]. A recent study indicated that E2F1-dependent tumor progression was triggered by the activation of the cytoplasmic Ras/Raf signaling cascades, such as the PI3K-AKT [16] and MEK-ERK pathways [19], most of which regulate cell proliferation, survival and invasion [20], [21]. Thus, we investigated t whether miR-493 regulates these pathways by targeting E2F1. The upregulation of miR-493, via the transfection of miR-493, in 95D and H1975 cells decreased the phosphorylation levels of AKT and its downstream target GSK3β (figure 6A). Similarly, miR-493 also suppressed the levels of phosphorylated ERK (figure 6A). We also observed that the knockdown of miR-493 via transfection with anti-miR-493 in HBE, A549 and H1299 cells, in which the relative expression level of miR-493 was higher, increased the levels of phosphorylated AKT, GSK3b and ERK (figure 6B). These western blotting results demonstrated that miR-493 is negative regulator of the AKT and ERK pathways. Subsequently, rescue experiments were performed by overexpressing the E2F1-Δ3′- UTR vector (without an endogenous 3′-UTR) in miR-493-treated cells. The miR-493-induced downregulation of E2F1 was rescued upon the introduction of E2F1 (figure 6C), and the phosphorylation levels of AKT and ERK were altered in a similar manner. These observations suggest that miR-493 inhibits the AKT and ERK pathways by targeting E2F1.

Bottom Line: Our data indicated that the expression of miR-493 was markedly reduced in pulmonary carcinoma.The ectopic expression of miR-493 impaired cell growth and invasion in vitro and in vivo.Mechanically, miR-493 commonly directly targeted E2F1, which resulted in a robust reduction of the expression of mRNA and protein.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research Institute and Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong, PR China; Medical School, University of South China, Hengyang, Hunan, PR China.

ABSTRACT
miRNAs have been proposed to be key regulators of progression and metastasis in cancer. However, an understanding of their roles and molecular mechanisms is needed to provide deeper insights for better therapeutic opportunities. In this study we investigated the role and mechanism of miR-493 in the development and progression of nonsmall-cell lung cancer (NSCLC). Our data indicated that the expression of miR-493 was markedly reduced in pulmonary carcinoma. The ectopic expression of miR-493 impaired cell growth and invasion in vitro and in vivo. Mechanically, miR-493 commonly directly targeted E2F1, which resulted in a robust reduction of the expression of mRNA and protein. This effect, in turn, decreased the growth, invasion and metastasis of lung cancer cells. Our findings highlight the importance of miR-493 dysfunction in promoting tumor progression, and implicate miR-493 as a potential therapeutic target in lung cancer.

Show MeSH
Related in: MedlinePlus