Abstract
Mus spretus mice are highly resistant to several types of cancer compared to Mus musculus mice. To determine whether differences in microRNA (miRNA) expression account for some of the differences in observed skin cancer susceptibility between the strains, we performed miRNA expression profiling of skin RNA for over 300 miRNAs. Five miRNAs, miR-1, miR-124a-3, miR-133a, miR-134, miR-206, were differentially expressed by array and/or qPCR. miR-1 was previously shown to have tumor suppressing abilities in multiple tumor types. We found miR-1 expression to be lower in mouse cutaneous squamous cell carcinomas (cSCCs) compared to normal skin. Based on the literature and our expression data, we performed detailed studies on predicted miR-1 targets and evaluated the effect of miR-1 expression on two murine cSCC cell lines, A5 and B9. Following transfection of miR-1, we found decreased mRNA expression of three validated miR-1 targets, Met, Twf1 and Ets1 and one novel target Bag4. Decreased expression of Ets1 was confirmed by Western analysis and by 3’ reporter luciferase assays containing wildtype and mutated Ets1 3’UTR. We evaluated the effect of miR-1 on multiple tumor phenotypes including apoptosis, proliferation, cell cycle and migration. In A5 cells, expression of miR-1 led to decreased proliferation compared to a control miR. miR-1 expression also led to increased apoptosis at later time points (72 and 96 h) and to a decrease in cells in S-phase. In summary, we identified five miRNAs with differential expression between cancer resistant and cancer susceptible mice and found that miR-1, a candidate tumor suppressor, has targets with defined roles in tumorigenesis.
Highlights
Mus Spretus mice are resistant to several cancer types including skin, colon, lung and thymic lymphoma (Nagase et al, 1995; Manenti et al, 1996; Villa-Morales, Santos & Fernandez-Piqueras, 2006; Huang et al, 2007)
To identify miRNAs that were differentially expressed between cancer resistant SPRET/EiJ and cancer susceptible FVB/NJ mice, we performed miRNA expression profiling of total RNA isolated from four normal skin samples per strain
Exploitation of genetic differences between cancer resistant and cancer susceptible mice has led to the identification of candidate genes important in tumorigenesis, but little has been explored regarding the differences in miRNA expression profiles in these mice
Summary
Mus Spretus mice are resistant to several cancer types including skin, colon, lung and thymic lymphoma (Nagase et al, 1995; Manenti et al, 1996; Villa-Morales, Santos & Fernandez-Piqueras, 2006; Huang et al, 2007). MicroRNAs (miRNAs) are short RNAs of 20-22 nucleotides with well-documented roles in gene regulation (Siomi & Siomi, 2010) They bind to the 3’untranslated region (3’UTR) of genes and may be involved in binding to other parts of the mRNA as well (Wery, Kwapisz & Morillon, 2011). Expression profiling studies have demonstrated that many miRNAs are down-regulated during tumor development, resulting in subsequent up-regulation of their target genes and respective proteins. These miRNAs act as tumor suppressors and target cell cycle, apoptosis, proliferation, invasion and metastasis genes (Croce, 2009). Previous studies indicate that several miRNAs map in close proximity to mouse QTLs for cancer susceptibility suggesting that variations in miRNA sequence or expression may be important for cancer susceptibility (Sevignani et al, 2007)
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