Krebswissenschaft und -therapie

Integrative Analysis of Transcriptome and MicroRNome Profiles in Cholangiocarcinoma

Abstract

Fábio E Severino, Claudia N Hasimoto, Maria A M Rodrigues, Juan C Llanos and Patricia P Reis

Aim: To identify deregulated expression of miRNAs and target genes in cholangiocarcinoma (CCA), as well as drug-gene interactions that may be useful for patient treatment.

Methods: We analyzed quantitative transcriptome and miRNA deep sequencing expression data from 45 samples, 36 CCA and 9 histologically normal biliary tissues, obtained from the public repository The Cancer Genome Atlas (TCGA). Bioinformatic methods were used to identify and integrate differential expression of miRNA and transcriptome profiles in CCA vs. normal tissues. Deregulated miRNA and corresponding target genes were identified and mapped into miRNA-mRNA networks.

Results: Results showed 64 differentially expressed miRNAs (48 over and 16 under-expressed) between CCA and corresponding normal biliary tissues. Additionally, 432 genes (180 over and 252 under-expressed) were identified between CCA and normal samples. We identified individual miRNAs with the largest number of gene targets. Among these, miR-125a was over-expressed and had the highest number of direct interactions with 33 mRNA targets. miRNAs miR-122 and miR-139 were the under-expressed miRNAs with the highest number of interactions (9 targets each). miR-122 was found to modulate the expression of the transcription factor FOXM1, known to be involved in tumorigenesis and the matrix metalloproteinase MMP7, an important mediator of tumor invasion. miR-148 and miR-194 were predicted to modulate NQO1, which is up-regulated in cancer and associated with treatment resistance in cholangiocarcinoma.

Conclusion: The novelty of our study is the identification of complex deregulated networks of miRNAs and target genes in CCA. miRNAs with a large number of targets may have a higher functional impact on cell regulation. These findings contribute for a better understanding of CCA biology. Identified miRNAs and target genes are potential candidates for the design of validation strategies towards the characterization of clinically applicable biomarkers; such biomarkers may be useful for the development of molecularly-targeted therapeutics that can benefit patients.