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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 expression levels are frequently downregulated in human lung cancer and associated with Prognosis.(A) The relative expression levels of miR-493 in 6 cell lines derived from lung cancer and one lung fibroblast line (MRC5), as well as an immortalized human bronchial epithelial cell (HBE) were determined by qRT-PCR. The data are presented as means ± SEM from at least 3 separate experiments.* p<0.05, **p<0.01. (B) The miR-493 expression levels in 65 paired human NSLCC and corresponding normal tissues were examined by real-time PCR, using GAPDH as an internal control. The expression value (ΔCt(N)- ΔCt(T)) represents the difference of in the miR-493 levels between normal tissue and tumor. A expression value >1 indicates that the miR-493 levels is increased in tumors. A expression value <1 indicates that the miR-493 levels is decreased in tumors. A paired t test (univariate) was used to compare the difference of between the normal group and cancer group. (C) Low levels of miR-493 correlates with shorter survival. The OS and DFS curves for all studied patients with high or lowmiR-493 expression.
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pone-0102602-g001: miR-493 expression levels are frequently downregulated in human lung cancer and associated with Prognosis.(A) The relative expression levels of miR-493 in 6 cell lines derived from lung cancer and one lung fibroblast line (MRC5), as well as an immortalized human bronchial epithelial cell (HBE) were determined by qRT-PCR. The data are presented as means ± SEM from at least 3 separate experiments.* p<0.05, **p<0.01. (B) The miR-493 expression levels in 65 paired human NSLCC and corresponding normal tissues were examined by real-time PCR, using GAPDH as an internal control. The expression value (ΔCt(N)- ΔCt(T)) represents the difference of in the miR-493 levels between normal tissue and tumor. A expression value >1 indicates that the miR-493 levels is increased in tumors. A expression value <1 indicates that the miR-493 levels is decreased in tumors. A paired t test (univariate) was used to compare the difference of between the normal group and cancer group. (C) Low levels of miR-493 correlates with shorter survival. The OS and DFS curves for all studied patients with high or lowmiR-493 expression.

Mentions: To identify the dysregulation of miRNA-493 in lung cancer, we examined the expression of miR-493 using real-time PCR in 6 cell lines derived from lung cancer and one lung fibroblast line (MRC5); as well as an immortalized human bronchial epithelial cell (HBE). The data indicated that miR-493 expression was significantly reduced in lung cancer cells, especially in 95D, a highly metastatic lung cancer cell line (figure 1A). Furthermore, we compared the miRNA-493 expression levels in 65 fresh lung cancer tissues by real-time PCR. Similarly, the expression of miR-493 was significantly lower in lung cancer tissues than in corresponding normal lung tissues (figure 1B). To determine whether the downregulation of miR-493 impacts the lung cancer phenotypes or clinical pathological features, we employed a correlation analysis and found that miR-493 expression level was inversely correlated with tumor metastasis (p = 0.038), but not other pathological parameters such as the clinical stage (table 1). In addition, a Kaplan–Meier survival analysis was conducted using patient overall survival (OS, figure 1C) and disease-free survival (DFS; figure 1D) to analyze the significance of miR-493 further in terms of clinical prognosis. The results showed that patients with low miR-493 expression had a shorter mean OS and DFS than patients with high miR-493 expression (P = 0.006 for OS, P = 0.000 for DFS; figure 1C and D). These data suggest that the downregulation of miR-493 contributes to lung cancer carcinogenesis and prognosis.


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 expression levels are frequently downregulated in human lung cancer and associated with Prognosis.(A) The relative expression levels of miR-493 in 6 cell lines derived from lung cancer and one lung fibroblast line (MRC5), as well as an immortalized human bronchial epithelial cell (HBE) were determined by qRT-PCR. The data are presented as means ± SEM from at least 3 separate experiments.* p<0.05, **p<0.01. (B) The miR-493 expression levels in 65 paired human NSLCC and corresponding normal tissues were examined by real-time PCR, using GAPDH as an internal control. The expression value (ΔCt(N)- ΔCt(T)) represents the difference of in the miR-493 levels between normal tissue and tumor. A expression value >1 indicates that the miR-493 levels is increased in tumors. A expression value <1 indicates that the miR-493 levels is decreased in tumors. A paired t test (univariate) was used to compare the difference of between the normal group and cancer group. (C) Low levels of miR-493 correlates with shorter survival. The OS and DFS curves for all studied patients with high or lowmiR-493 expression.
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Related In: Results  -  Collection

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

pone-0102602-g001: miR-493 expression levels are frequently downregulated in human lung cancer and associated with Prognosis.(A) The relative expression levels of miR-493 in 6 cell lines derived from lung cancer and one lung fibroblast line (MRC5), as well as an immortalized human bronchial epithelial cell (HBE) were determined by qRT-PCR. The data are presented as means ± SEM from at least 3 separate experiments.* p<0.05, **p<0.01. (B) The miR-493 expression levels in 65 paired human NSLCC and corresponding normal tissues were examined by real-time PCR, using GAPDH as an internal control. The expression value (ΔCt(N)- ΔCt(T)) represents the difference of in the miR-493 levels between normal tissue and tumor. A expression value >1 indicates that the miR-493 levels is increased in tumors. A expression value <1 indicates that the miR-493 levels is decreased in tumors. A paired t test (univariate) was used to compare the difference of between the normal group and cancer group. (C) Low levels of miR-493 correlates with shorter survival. The OS and DFS curves for all studied patients with high or lowmiR-493 expression.
Mentions: To identify the dysregulation of miRNA-493 in lung cancer, we examined the expression of miR-493 using real-time PCR in 6 cell lines derived from lung cancer and one lung fibroblast line (MRC5); as well as an immortalized human bronchial epithelial cell (HBE). The data indicated that miR-493 expression was significantly reduced in lung cancer cells, especially in 95D, a highly metastatic lung cancer cell line (figure 1A). Furthermore, we compared the miRNA-493 expression levels in 65 fresh lung cancer tissues by real-time PCR. Similarly, the expression of miR-493 was significantly lower in lung cancer tissues than in corresponding normal lung tissues (figure 1B). To determine whether the downregulation of miR-493 impacts the lung cancer phenotypes or clinical pathological features, we employed a correlation analysis and found that miR-493 expression level was inversely correlated with tumor metastasis (p = 0.038), but not other pathological parameters such as the clinical stage (table 1). In addition, a Kaplan–Meier survival analysis was conducted using patient overall survival (OS, figure 1C) and disease-free survival (DFS; figure 1D) to analyze the significance of miR-493 further in terms of clinical prognosis. The results showed that patients with low miR-493 expression had a shorter mean OS and DFS than patients with high miR-493 expression (P = 0.006 for OS, P = 0.000 for DFS; figure 1C and D). These data suggest that the downregulation of miR-493 contributes to lung cancer carcinogenesis and prognosis.

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