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The microRNA-218~Survivin axis regulates migration, invasion, and lymph node metastasis in cervical cancer.

Kogo R, How C, Chaudary N, Bruce J, Shi W, Hill RP, Zahedi P, Yip KW, Liu FF - Oncotarget (2015)

Bottom Line: Lower miR-218 expression was associated significantly with worse overall survival (OS), disease-free survival (DFS), and pelvic/aortic lymph node recurrence.In vitro, miR-218 over-expression decreased clonogenicity, migration, and invasion.YM155, a small molecule survivin inhibitor, significantly suppressed tumor growth and lymph node metastasis in vivo.

View Article: PubMed Central - PubMed

Affiliation: Ontario Cancer Institute, University Health Network (UHN), Toronto, Ontario, Canada.

ABSTRACT
Cervical cancer is the third most common cancer in women worldwide. In the present study, global microRNA profiling for 79 cervical cancer patient samples led to the identification of miR-218 down-regulation in cervical cancer tissues compared to normal cervical tissues. Lower miR-218 expression was associated significantly with worse overall survival (OS), disease-free survival (DFS), and pelvic/aortic lymph node recurrence. In vitro, miR-218 over-expression decreased clonogenicity, migration, and invasion. Survivin (BIRC5) was subsequently identified as an important cervical cancer target of miR-218 using in silico prediction, mRNA profiling, and quantitative real-time PCR (qRT-PCR). Concordant with miR-218 over-expression, survivin knockdown by siRNA decreased clonogenicity, migration, and invasion. YM155, a small molecule survivin inhibitor, significantly suppressed tumor growth and lymph node metastasis in vivo. Our findings demonstrate that the miR-218~survivin axis inhibits cervical cancer progression by regulating clonogenicity, migration, and invasion, and suggest that the inhibition of survivin could be a potential therapeutic strategy to improve outcome in this disease.

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miR-218 down-regulation is associated with poor survival in cervical cancer patientsA) miR-218 expression in 79 cervical cancer patient samples and 11 normal cervix epithelial samples. miR-218 expression (log2) was measured using Taqman Low Density Array (TLDA) Human MicroRNA A Arrays V2.0 for 79 cervical cancer tissues and 11 normal cervix tissues. B) Kaplan-Meier analysis of overall (left) and disease-free survival (right) in 79 cervical cancer patients. Solid line: miR-218 high expression group (n=35); dotted line: miR-218 low expression group (n=44). C) Genomic alteration of miR-218 loci (left: hsa-miR-218-1, chromosome 4p15.31; right: hsa-miR-218-2, chromosome 5q34) using copy number data from 105 cervical squamous cell carcinoma samples generated by TCGA using SNP 6.0 arrays. Genomic alteration was visualized using the IGV (Integrative Genomic Viewer, Broad Institute). Blue represents genomic deletion and red represents genomic amplification.
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Figure 1: miR-218 down-regulation is associated with poor survival in cervical cancer patientsA) miR-218 expression in 79 cervical cancer patient samples and 11 normal cervix epithelial samples. miR-218 expression (log2) was measured using Taqman Low Density Array (TLDA) Human MicroRNA A Arrays V2.0 for 79 cervical cancer tissues and 11 normal cervix tissues. B) Kaplan-Meier analysis of overall (left) and disease-free survival (right) in 79 cervical cancer patients. Solid line: miR-218 high expression group (n=35); dotted line: miR-218 low expression group (n=44). C) Genomic alteration of miR-218 loci (left: hsa-miR-218-1, chromosome 4p15.31; right: hsa-miR-218-2, chromosome 5q34) using copy number data from 105 cervical squamous cell carcinoma samples generated by TCGA using SNP 6.0 arrays. Genomic alteration was visualized using the IGV (Integrative Genomic Viewer, Broad Institute). Blue represents genomic deletion and red represents genomic amplification.

Mentions: Analysis of Taqman Low Density Array (TLDA) data determined that expression of miR-218 was significantly reduced in 79 cervical cancer tissues compared to 11 normal cervix tissues (P<0.001; Figure 1A). Further details of this study have been described in How et al. [17]; in brief, these patients have all been treated for cure (radiation and chemotherapy) with a median follow-up time of 6 years. We therefore investigated the association between miR-218 expression with patient survival. Initially, the median miR-218 expression value was utilized to divide the 79 cervical cancer patients into high vs. low expression groups (miR-218 highmedian, n=39; miR-218 lowmedian, n=40). The miR-218 low expression group experienced a worse overall survival (OS), and disease-free survival (DFS) (OS P=0.074; DFS P=0.079, Figure S1), but the data were of borderline statistical significance. The groups were then re-divided, based on the lowest level of miR-218 expression measured in the normal cervix population. This resulted in 35 patients with high miR-218 expression vs. 44 with low miR-218 expression. Using this new cut-off level, the low miR-218 expression group experienced a significantly poorer outcome with regards to both OS and DFS (OS P=0.009; DFS P=0.014; Figure 1B). These data suggest that cervical cancer patients with lower miR-218 expression levels than detected in normal cervical epithelium tissues will experience a poor outcome.


The microRNA-218~Survivin axis regulates migration, invasion, and lymph node metastasis in cervical cancer.

Kogo R, How C, Chaudary N, Bruce J, Shi W, Hill RP, Zahedi P, Yip KW, Liu FF - Oncotarget (2015)

miR-218 down-regulation is associated with poor survival in cervical cancer patientsA) miR-218 expression in 79 cervical cancer patient samples and 11 normal cervix epithelial samples. miR-218 expression (log2) was measured using Taqman Low Density Array (TLDA) Human MicroRNA A Arrays V2.0 for 79 cervical cancer tissues and 11 normal cervix tissues. B) Kaplan-Meier analysis of overall (left) and disease-free survival (right) in 79 cervical cancer patients. Solid line: miR-218 high expression group (n=35); dotted line: miR-218 low expression group (n=44). C) Genomic alteration of miR-218 loci (left: hsa-miR-218-1, chromosome 4p15.31; right: hsa-miR-218-2, chromosome 5q34) using copy number data from 105 cervical squamous cell carcinoma samples generated by TCGA using SNP 6.0 arrays. Genomic alteration was visualized using the IGV (Integrative Genomic Viewer, Broad Institute). Blue represents genomic deletion and red represents genomic amplification.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4359219&req=5

Figure 1: miR-218 down-regulation is associated with poor survival in cervical cancer patientsA) miR-218 expression in 79 cervical cancer patient samples and 11 normal cervix epithelial samples. miR-218 expression (log2) was measured using Taqman Low Density Array (TLDA) Human MicroRNA A Arrays V2.0 for 79 cervical cancer tissues and 11 normal cervix tissues. B) Kaplan-Meier analysis of overall (left) and disease-free survival (right) in 79 cervical cancer patients. Solid line: miR-218 high expression group (n=35); dotted line: miR-218 low expression group (n=44). C) Genomic alteration of miR-218 loci (left: hsa-miR-218-1, chromosome 4p15.31; right: hsa-miR-218-2, chromosome 5q34) using copy number data from 105 cervical squamous cell carcinoma samples generated by TCGA using SNP 6.0 arrays. Genomic alteration was visualized using the IGV (Integrative Genomic Viewer, Broad Institute). Blue represents genomic deletion and red represents genomic amplification.
Mentions: Analysis of Taqman Low Density Array (TLDA) data determined that expression of miR-218 was significantly reduced in 79 cervical cancer tissues compared to 11 normal cervix tissues (P<0.001; Figure 1A). Further details of this study have been described in How et al. [17]; in brief, these patients have all been treated for cure (radiation and chemotherapy) with a median follow-up time of 6 years. We therefore investigated the association between miR-218 expression with patient survival. Initially, the median miR-218 expression value was utilized to divide the 79 cervical cancer patients into high vs. low expression groups (miR-218 highmedian, n=39; miR-218 lowmedian, n=40). The miR-218 low expression group experienced a worse overall survival (OS), and disease-free survival (DFS) (OS P=0.074; DFS P=0.079, Figure S1), but the data were of borderline statistical significance. The groups were then re-divided, based on the lowest level of miR-218 expression measured in the normal cervix population. This resulted in 35 patients with high miR-218 expression vs. 44 with low miR-218 expression. Using this new cut-off level, the low miR-218 expression group experienced a significantly poorer outcome with regards to both OS and DFS (OS P=0.009; DFS P=0.014; Figure 1B). These data suggest that cervical cancer patients with lower miR-218 expression levels than detected in normal cervical epithelium tissues will experience a poor outcome.

Bottom Line: Lower miR-218 expression was associated significantly with worse overall survival (OS), disease-free survival (DFS), and pelvic/aortic lymph node recurrence.In vitro, miR-218 over-expression decreased clonogenicity, migration, and invasion.YM155, a small molecule survivin inhibitor, significantly suppressed tumor growth and lymph node metastasis in vivo.

View Article: PubMed Central - PubMed

Affiliation: Ontario Cancer Institute, University Health Network (UHN), Toronto, Ontario, Canada.

ABSTRACT
Cervical cancer is the third most common cancer in women worldwide. In the present study, global microRNA profiling for 79 cervical cancer patient samples led to the identification of miR-218 down-regulation in cervical cancer tissues compared to normal cervical tissues. Lower miR-218 expression was associated significantly with worse overall survival (OS), disease-free survival (DFS), and pelvic/aortic lymph node recurrence. In vitro, miR-218 over-expression decreased clonogenicity, migration, and invasion. Survivin (BIRC5) was subsequently identified as an important cervical cancer target of miR-218 using in silico prediction, mRNA profiling, and quantitative real-time PCR (qRT-PCR). Concordant with miR-218 over-expression, survivin knockdown by siRNA decreased clonogenicity, migration, and invasion. YM155, a small molecule survivin inhibitor, significantly suppressed tumor growth and lymph node metastasis in vivo. Our findings demonstrate that the miR-218~survivin axis inhibits cervical cancer progression by regulating clonogenicity, migration, and invasion, and suggest that the inhibition of survivin could be a potential therapeutic strategy to improve outcome in this disease.

Show MeSH
Related in: MedlinePlus