Abstract
Uncontrolled cell replication is a key component of carcinogenesis. MicroRNAs (miRNAs) regulate genes involved in checkpoints, DNA repair, and genes encoding for key proteins regulating the cell cycle. We investigated how miRNAs and mRNAs in colorectal cancer subjects interact to regulate the cell cycle.Using RNA-Seq data from 217 individuals, we analyzed differential expression (carcinoma minus normal mucosa) of 123 genes within the cell cycle pathway with differential miRNA expression, adjusting for age and sex. Multiple comparison adjustments for gene/miRNA associations were made at the gene level using an FDR <0.05. Differentially expressed miRNAs and mRNAs were tested for associations with colorectal cancer survival. MRNA and miRNA sequences were compared to identify seed region matches to support biological interpretation of the observed associations.Sixty-seven mRNAs were dysregulated with a fold change (FC) <0.67 or >1.50. Thirty-two mRNAs were associated with 48 miRNAs; 102 of 290 total associations had identified seed matches; of these, ten had negative beta coefficients. Hsa-miR-15a-5p and hsa-miR-20b-5p were associated with colorectal cancer survival with an FDR <0.05 (HR 0.86 95% CI 0.79, 0.94; HR 0.83 95% CI 0.75, 0.91 respectively).Our findings suggest that miRNAs impact mRNA translation at multiple levels within the cell cycle.
Highlights
The eukaryotic cell cycle can be divided in four major phases: G1, Synthesis (S), in which DNA is synthesized, G2, and Mitosis (M)
cyclin-dependent kinases (CDKs), which are serine/ threonine kinases, are the catalytic subunits expressed in relatively stable amounts throughout the cell cycle [2]; it is their association with specific cyclins that determines whether the cell cycle progresses
Of the 124 cell cycle genes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) repository, 110 were statistically significantly differentially expressed for overall colorectal cancer after adjustment for multiple comparisons. Nineteen of these genes were downregulated in carcinoma tissue compared to normal colorectal mucosa, four of these with a fold change (FC) < 0.67
Summary
The eukaryotic cell cycle can be divided in four major phases: G1, Synthesis (S), in which DNA is synthesized, G2, and Mitosis (M). Progression from one phase of the cell cycle to the is controlled principally by a family of proteins called cyclins, which bind with and activate cyclin-dependent kinases (CDKs). Cyclins and CDKs form heterodimeric protein kinase complexes that are crucial for regulating specific steps in the cell cycle. Cyclins, which increase and decrease in concentration during different steps in the cell cycle, are the regulatory subunit of the complexes [1]. CDKs, which are serine/ threonine kinases, are the catalytic subunits expressed in relatively stable amounts throughout the cell cycle [2]; it is their association with specific cyclins that determines whether the cell cycle progresses. CDKs have no catalytic activity of their own and so must be associated with a cyclin to phosphorylate different proteins
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