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miRNAs associated with chemo-sensitivity in cell lines and in advanced bladder cancer.

Nordentoft I, Birkenkamp-Demtroder K, Agerbæk M, Theodorescu D, Ostenfeld MS, Hartmann A, Borre M, Ørntoft TF, Dyrskjøt L - BMC Med Genomics (2012)

Bottom Line: Three miRNAs were associated with both response and survival (886-3p, 923, 944).By changing the cellular level of the response-identified miRNAs in eight bladder cell lines with different cisplatin sensitivity we found that down-regulation of miR-27a, miR296-5p and miR-642 generally reduced the cell viability, whereas up-regulation of miR-138 and miR-886-3p reduced the viability of more than half of the cell lines.Decreasing miR-138 increased the cisplatin sensitivity in half of the cell lines and increasing miR-27a and miR-642 generally increased cisplatin sensitivity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. iver.nordentoft@ki.au.dk

ABSTRACT

Background: MicroRNA is a naturally occurring class of non-coding RNA molecules that mediate posttranscriptional gene regulation and are strongly implicated in cellular processes such as cell proliferation, carcinogenesis, cell survival and apoptosis. Consequently there is increasing focus on miRNA expression as prognostic factors for outcome and chemotherapy response. Only approximately 50% of patients with bladder cancer respond to chemotherapy. Therefore, predictive markers, such as miRNAs, that can identify subgroups of patients who will benefit from chemotherapy will have great value for treatment guidance.

Methods: We profiled the expression of 671 miRNAs in formalin fixed paraffin embedded tumors from patients with advanced bladder cancer treated with cisplatin based chemotherapy. We delineated differentially expressed miRNAs in tumors from patients with complete response vs. patients with progressive disease and in tumors form patients with short and long overall survival time. Furthermore, we studied the effect of up- and down regulation of key miRNAs on the cisplatin sensitivity in eight bladder cancer cell lines with different sensitivities to cisplatin.

Results: miRNA expression profiling identified 15 miRNAs that correlated with response to chemotherapy and 5 miRNAs that correlated with survival time. Three miRNAs were associated with both response and survival (886-3p, 923, 944). By changing the cellular level of the response-identified miRNAs in eight bladder cell lines with different cisplatin sensitivity we found that down-regulation of miR-27a, miR296-5p and miR-642 generally reduced the cell viability, whereas up-regulation of miR-138 and miR-886-3p reduced the viability of more than half of the cell lines. Decreasing miR-138 increased the cisplatin sensitivity in half of the cell lines and increasing miR-27a and miR-642 generally increased cisplatin sensitivity.

Conclusions: MiRNAs seem to be involved in cisplatin based chemo response and may form a new target for therapy and serve as biomarkers for treatment response.

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Related in: MedlinePlus

Heatmaps of miRNA expression patterns. miRNA expression is depicted according to (A) treatment response and (B) overall survival. Yellow; upregulation of the gene, blue; downregulation, black; median expression, grey; missing value.
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Figure 1: Heatmaps of miRNA expression patterns. miRNA expression is depicted according to (A) treatment response and (B) overall survival. Yellow; upregulation of the gene, blue; downregulation, black; median expression, grey; missing value.

Mentions: We profiled the expression of 671 miRNAs in tumors from patients with advanced bladder cancer subsequently treated with cisplatin based chemotherapy (Table 1 and Additional file 1: Table S1). Seven patients experienced progression of disease (PD) and eight patients experienced complete responses (CR) according to the RECIST criteria [23]. Differentially expressed miRNAs (PD vs.CR) are listed in Table 2. The expression levels of the 15 top ranked miRNAs in the different tumors samples are shown in Figure 1A. Data was normalized using miRNA-193b as this was identified as the most stably expressed miRNA across all samples by Norm Finder [24]. Different normalization approaches showed highly similar results (Additional file 3: Table S3). As a technical evaluation of the Taqman Human Array MicroRNA Cards we selected the 5 top ranked miRNAs from the analysis (miRNA-642, 492, 27a, 296-5p, 944, 193a-5p) and performed single-plex qRT-PCR. The qRT-PCR fully confirmed the Taqman Human Array MicroRNA results (Additional file 4: Table S4). Interestingly, the analysis showed that the majority of top ranked miRNAs had a reduced expression in the CR group compared to the PD group. The chromosome location of the 15 differentially expressed miRNAs (Table 2) shows that the unidirectional expression pattern is not due to regional epigenetically silencing of the miRNAs.


miRNAs associated with chemo-sensitivity in cell lines and in advanced bladder cancer.

Nordentoft I, Birkenkamp-Demtroder K, Agerbæk M, Theodorescu D, Ostenfeld MS, Hartmann A, Borre M, Ørntoft TF, Dyrskjøt L - BMC Med Genomics (2012)

Heatmaps of miRNA expression patterns. miRNA expression is depicted according to (A) treatment response and (B) overall survival. Yellow; upregulation of the gene, blue; downregulation, black; median expression, grey; missing value.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3473298&req=5

Figure 1: Heatmaps of miRNA expression patterns. miRNA expression is depicted according to (A) treatment response and (B) overall survival. Yellow; upregulation of the gene, blue; downregulation, black; median expression, grey; missing value.
Mentions: We profiled the expression of 671 miRNAs in tumors from patients with advanced bladder cancer subsequently treated with cisplatin based chemotherapy (Table 1 and Additional file 1: Table S1). Seven patients experienced progression of disease (PD) and eight patients experienced complete responses (CR) according to the RECIST criteria [23]. Differentially expressed miRNAs (PD vs.CR) are listed in Table 2. The expression levels of the 15 top ranked miRNAs in the different tumors samples are shown in Figure 1A. Data was normalized using miRNA-193b as this was identified as the most stably expressed miRNA across all samples by Norm Finder [24]. Different normalization approaches showed highly similar results (Additional file 3: Table S3). As a technical evaluation of the Taqman Human Array MicroRNA Cards we selected the 5 top ranked miRNAs from the analysis (miRNA-642, 492, 27a, 296-5p, 944, 193a-5p) and performed single-plex qRT-PCR. The qRT-PCR fully confirmed the Taqman Human Array MicroRNA results (Additional file 4: Table S4). Interestingly, the analysis showed that the majority of top ranked miRNAs had a reduced expression in the CR group compared to the PD group. The chromosome location of the 15 differentially expressed miRNAs (Table 2) shows that the unidirectional expression pattern is not due to regional epigenetically silencing of the miRNAs.

Bottom Line: Three miRNAs were associated with both response and survival (886-3p, 923, 944).By changing the cellular level of the response-identified miRNAs in eight bladder cell lines with different cisplatin sensitivity we found that down-regulation of miR-27a, miR296-5p and miR-642 generally reduced the cell viability, whereas up-regulation of miR-138 and miR-886-3p reduced the viability of more than half of the cell lines.Decreasing miR-138 increased the cisplatin sensitivity in half of the cell lines and increasing miR-27a and miR-642 generally increased cisplatin sensitivity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. iver.nordentoft@ki.au.dk

ABSTRACT

Background: MicroRNA is a naturally occurring class of non-coding RNA molecules that mediate posttranscriptional gene regulation and are strongly implicated in cellular processes such as cell proliferation, carcinogenesis, cell survival and apoptosis. Consequently there is increasing focus on miRNA expression as prognostic factors for outcome and chemotherapy response. Only approximately 50% of patients with bladder cancer respond to chemotherapy. Therefore, predictive markers, such as miRNAs, that can identify subgroups of patients who will benefit from chemotherapy will have great value for treatment guidance.

Methods: We profiled the expression of 671 miRNAs in formalin fixed paraffin embedded tumors from patients with advanced bladder cancer treated with cisplatin based chemotherapy. We delineated differentially expressed miRNAs in tumors from patients with complete response vs. patients with progressive disease and in tumors form patients with short and long overall survival time. Furthermore, we studied the effect of up- and down regulation of key miRNAs on the cisplatin sensitivity in eight bladder cancer cell lines with different sensitivities to cisplatin.

Results: miRNA expression profiling identified 15 miRNAs that correlated with response to chemotherapy and 5 miRNAs that correlated with survival time. Three miRNAs were associated with both response and survival (886-3p, 923, 944). By changing the cellular level of the response-identified miRNAs in eight bladder cell lines with different cisplatin sensitivity we found that down-regulation of miR-27a, miR296-5p and miR-642 generally reduced the cell viability, whereas up-regulation of miR-138 and miR-886-3p reduced the viability of more than half of the cell lines. Decreasing miR-138 increased the cisplatin sensitivity in half of the cell lines and increasing miR-27a and miR-642 generally increased cisplatin sensitivity.

Conclusions: MiRNAs seem to be involved in cisplatin based chemo response and may form a new target for therapy and serve as biomarkers for treatment response.

Show MeSH
Related in: MedlinePlus