Abstract
miRNAs constitute a class of non-coding RNA that act as powerful epigenetic regulators in animal and plant cells. In order to identify putative tumor-suppressor miRNAs we profiled the expression of various miRNAs during differentiation of erythroleukemia cells. RNA was purified before and after differentiation induction and subjected to quantitative RT-PCR. The majority of the miRNAs tested were found upregulated in differentiated cells with miR-16-5p showing the most significant increase. Functional studies using gain- and loss-of-function constructs proposed that miR-16-5p has a role in promoting the erythroid differentiation program of murine erythroleukemia (MEL) cells. In order to identify the underlying mechanism of action, we utilized bioinformatic in-silico platforms that incorporate predictions for the genes targeted by miR-16-5p. Interestingly, ribosome constituents, as well as ribosome biogenesis factors, were overrepresented among the miR-16-5p predicted gene targets. Accordingly, biochemical experiments showed that, indeed, miR-16-5p could modulate the levels of independent ribosomal proteins, and the overall ribosomal levels in cultured cells. In conclusion, miR-16-5p is identified as a differentiation-promoting agent in erythroleukemia cells, demonstrating antiproliferative activity, likely as a result of its ability to target the ribosomal machinery and restore any imbalanced activity imposed by the malignancy and the blockade of differentiation.
Highlights
MicroRNAs have been implicated in all major biological processes that govern the metabolism and function of cells as well as the life of organisms
We focus on miR-165p, which showed a strong upregulation in differentiated murine erythroleukemia (MEL) cells
MicroRNAs are involved in almost every aspect of cancer cell biology acting either as oncogenes or as tumor-suppressors
Summary
MicroRNAs (miRNAs) have been implicated in all major biological processes that govern the metabolism and function of cells as well as the life of organisms. They regulate gene expression by base-pairing with complementary target mRNA molecules and typically induce RNA silencing. MiRNAs are found amplified or downregulated in cancer cells acting either as oncogenes (onco-miRs) or as tumor suppressor molecules [1,2,3,4,5]. MiR-21 is overexpressed in a variety of cancer cell types and promotes carcinogenesis by repressing the levels of tumor-suppressor genes such as, PTEN, FasL and PDCD4 [6,7]. The identification and characterization of novel oncosuppressor miRNAs for specific tumor types will advance the development of new anticancer therapeutic strategies
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