Functional genomics of microrna- directed regulation of tumorigenesis in human cancer cells
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In the past few decades, microRNAs emerged as key regulators of gene expression in many fundamental biological processes such as development and differentiation as well as diseases. There are thousands of microRNAs that have been discovered, and while plenty of them have been linked to diseases such as cancer, there is still much to discover; their genome-wide targets and functions to elucidate their potential as cancer biomarkers and therapeutic targets. This study provides an investigation of genome-wide effects of three microRNAs; mir-21, mir-9 and mir-9*, their functional roles and direct targets in breast cancer transcriptome. Consistent with the previous reports, the oncogenic activity of mir-21 in breast cancer cells has been confirmed. Microarray analysis of the knockdown of mir-21, a well-known oncomir shown in many cancer types, identified downregulation of the JAK-STAT pathway. A possible autoregulatory loop with direct interaction of mir-21 and STAT3 has been identified. In addition, a direct communication between mir-21 and JAG1 that involves estrogen signaling has been identified in breast cancer cells. Mir-9 is known to be frequently hypermethylated and downregulated in cancer samples. Functional analysis of mir-9 overexpression showed decreased cell proliferation and increased apoptosis. Microarray analysis of mir-9 expression restoration in cancer cells revealed many predicted targets as differentially regulated. A total of seven direct targets have been confirmed of which two of them involved in the anti-proliferative activity of mir-9. Moreover, a gene/pseudogene pair has been identified as direct mir-9 targets. CSDAP1, pseudogene of CSDA, acts as mir-9 decoy in MCF-7 cells. Mir-9* is processed as the minor product of MIRN9 precursor which also generates mir-9. Its expression is lower than mir-9 in cancer cells although shows higher expression in MCF-7 cells compared to normal breast tissue. Functional analysis of mir-9* overexpression revealed an oncogenic potential in breast cancer cells. Mir-9* 1 overexpressing cells showed faster cell proliferation, migration and more invasiveness. Microarray profiling of mir-9* overexpression identified many predicted targets as differentially regulated. Twelve of selected direct or indirect targets have been confirmed. Using microarray profiling, this study elucidates genome-wide effects of three microRNAs. Functional experiments revealed further insights regarding the phenotypic effects of microRNA dosage perturbations and direct targets of microRNAs in cancer cells. This study demonstrates the importance of microRNA dosage (expression levels) in cancer cells highlights the potential of microRNAs as biomarkers in cancer and contributes to the microRNA and cancer literature through identification of novel microRNA: mRNA interactions in cancer cells.