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Novel miRNA-mRNA interactions conserved in essential cancer pathways

View Article: PubMed Central - PubMed

ABSTRACT

Cancer is a complex disease in which unrestrained cell proliferation results in tumour development. Extensive research into the molecular mechanisms underlying tumorigenesis has led to the characterization of oncogenes and tumour suppressors that are key elements in cancer growth and progression, as well as that of other important elements like microRNAs. These genes and miRNAs appear to be constitutively deregulated in cancer. To identify signatures of miRNA-mRNA interactions potentially conserved in essential cancer pathways, we have conducted an integrative analysis of transcriptomic data, also taking into account methylation and copy number alterations. We analysed 18,605 raw transcriptome samples from The Cancer Genome Atlas covering 15 of the most common types of human tumours. From this global transcriptome study, we recovered known cancer-associated miRNA-targets and importantly, we identified new potential targets from miRNA families, also analysing the phenotypic outcomes of these genes/mRNAs in terms of survival. Further analyses could lead to novel approaches in cancer therapy.

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Related in: MedlinePlus

Survival with multifactorial Cox models in 15 tumours.Combined correlation and survival analysis for the selected 36 general miRNA-gene pairs. Every box summarizes the results of the correlation and survival analysis of a miRNA-gene pair (rows) in a particular cancer type (columns). Circles represent miRNA-gene expression correlations, after accounting for CNAs and gene methylation. Negative correlations in red, and positive correlations in blue. Diamonds represent the log2 of the hazard ratio (HR) of Cox proportional hazards models that included tumor stage (or tumor grade, in the case of PRAD) and the log-transformed gene expression values as explanatory variables. Positive log2(HR), i.e. shorter survival, in shades of red. Negative log2(HR), i.e. longer survival, in shades of blue. All P-values were corrected for multi-hypothesis testing by the FDR method. Pairs reaching statistical significance (Adj. P < 0.05) in both miRNA-gen expression correlation and gene expression-survival association are indicated with thicker boxes.
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f6: Survival with multifactorial Cox models in 15 tumours.Combined correlation and survival analysis for the selected 36 general miRNA-gene pairs. Every box summarizes the results of the correlation and survival analysis of a miRNA-gene pair (rows) in a particular cancer type (columns). Circles represent miRNA-gene expression correlations, after accounting for CNAs and gene methylation. Negative correlations in red, and positive correlations in blue. Diamonds represent the log2 of the hazard ratio (HR) of Cox proportional hazards models that included tumor stage (or tumor grade, in the case of PRAD) and the log-transformed gene expression values as explanatory variables. Positive log2(HR), i.e. shorter survival, in shades of red. Negative log2(HR), i.e. longer survival, in shades of blue. All P-values were corrected for multi-hypothesis testing by the FDR method. Pairs reaching statistical significance (Adj. P < 0.05) in both miRNA-gen expression correlation and gene expression-survival association are indicated with thicker boxes.

Mentions: The 36 pairs that exhibited a statistically significant negative correlation in the multivariate linear regression joint analysis (Supplementary Figure 1) were selected for a subsequent survival analyses (Fig. 6). The effect of gene expression on patient survival was explored separately for each cancer type using Cox proportional hazard models that included tumour stage. In these models, both tumour stage (encoded as one of two categories, i.e. Stage I-II vs Stage III-IV) and the log-transformed gene expression values were used as explanatory variables. Information on tumour stage was not available for prostate cancer (PRAD), so in this case tumour grade was employed as the explanatory variable (Gleason score 6–7 vs 8–10). Pairs that exhibited both a significant correlation between miRNA and gene expression, and a significant tumour stage-independent association between gene expression and patient survival, support the hypothesis that miRNA expression regulates gene expression and that the latter affects patient survival. We found miRNA-Gene Survival associations in 11 of the 36 selected pairs.


Novel miRNA-mRNA interactions conserved in essential cancer pathways
Survival with multifactorial Cox models in 15 tumours.Combined correlation and survival analysis for the selected 36 general miRNA-gene pairs. Every box summarizes the results of the correlation and survival analysis of a miRNA-gene pair (rows) in a particular cancer type (columns). Circles represent miRNA-gene expression correlations, after accounting for CNAs and gene methylation. Negative correlations in red, and positive correlations in blue. Diamonds represent the log2 of the hazard ratio (HR) of Cox proportional hazards models that included tumor stage (or tumor grade, in the case of PRAD) and the log-transformed gene expression values as explanatory variables. Positive log2(HR), i.e. shorter survival, in shades of red. Negative log2(HR), i.e. longer survival, in shades of blue. All P-values were corrected for multi-hypothesis testing by the FDR method. Pairs reaching statistical significance (Adj. P < 0.05) in both miRNA-gen expression correlation and gene expression-survival association are indicated with thicker boxes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384238&req=5

f6: Survival with multifactorial Cox models in 15 tumours.Combined correlation and survival analysis for the selected 36 general miRNA-gene pairs. Every box summarizes the results of the correlation and survival analysis of a miRNA-gene pair (rows) in a particular cancer type (columns). Circles represent miRNA-gene expression correlations, after accounting for CNAs and gene methylation. Negative correlations in red, and positive correlations in blue. Diamonds represent the log2 of the hazard ratio (HR) of Cox proportional hazards models that included tumor stage (or tumor grade, in the case of PRAD) and the log-transformed gene expression values as explanatory variables. Positive log2(HR), i.e. shorter survival, in shades of red. Negative log2(HR), i.e. longer survival, in shades of blue. All P-values were corrected for multi-hypothesis testing by the FDR method. Pairs reaching statistical significance (Adj. P < 0.05) in both miRNA-gen expression correlation and gene expression-survival association are indicated with thicker boxes.
Mentions: The 36 pairs that exhibited a statistically significant negative correlation in the multivariate linear regression joint analysis (Supplementary Figure 1) were selected for a subsequent survival analyses (Fig. 6). The effect of gene expression on patient survival was explored separately for each cancer type using Cox proportional hazard models that included tumour stage. In these models, both tumour stage (encoded as one of two categories, i.e. Stage I-II vs Stage III-IV) and the log-transformed gene expression values were used as explanatory variables. Information on tumour stage was not available for prostate cancer (PRAD), so in this case tumour grade was employed as the explanatory variable (Gleason score 6–7 vs 8–10). Pairs that exhibited both a significant correlation between miRNA and gene expression, and a significant tumour stage-independent association between gene expression and patient survival, support the hypothesis that miRNA expression regulates gene expression and that the latter affects patient survival. We found miRNA-Gene Survival associations in 11 of the 36 selected pairs.

View Article: PubMed Central - PubMed

ABSTRACT

Cancer is a complex disease in which unrestrained cell proliferation results in tumour development. Extensive research into the molecular mechanisms underlying tumorigenesis has led to the characterization of oncogenes and tumour suppressors that are key elements in cancer growth and progression, as well as that of other important elements like microRNAs. These genes and miRNAs appear to be constitutively deregulated in cancer. To identify signatures of miRNA-mRNA interactions potentially conserved in essential cancer pathways, we have conducted an integrative analysis of transcriptomic data, also taking into account methylation and copy number alterations. We analysed 18,605 raw transcriptome samples from The Cancer Genome Atlas covering 15 of the most common types of human tumours. From this global transcriptome study, we recovered known cancer-associated miRNA-targets and importantly, we identified new potential targets from miRNA families, also analysing the phenotypic outcomes of these genes/mRNAs in terms of survival. Further analyses could lead to novel approaches in cancer therapy.

No MeSH data available.


Related in: MedlinePlus