miR-223 regulates cell growth and targets proto-oncogenes in mycosis fungoides/cutaneous T-cell lymphoma

The pathogenesis of the cutaneous T-cell lymphoma (CTCL), mycosis fungoides (MF) is unclear. MicroRNA (miRNA) are small non-coding RNA that target mRNA leading to reduced mRNA translation. Recently, specific miRNA were shown to be altered in CTCL. We identified significantly reduced expression of miR-223 in early stage MF skin, and the levels of miR-223 diminished further in advanced stage disease. CTCL peripheral blood mononuclear cells and cell lines also had reduced miR-223 as compared to controls. Elevated expression of miR-223 in these cell lines reduced cell growth and clonogenic potential, whereas inhibition of miR-223 increased cell numbers. Investigations into putative miR-223 targets with oncogenic function, including E2F1 and MEF2C, and the predicted miR-223 target, TOX, revealed all three are targeted by miR-223 in CTCL. E2F1, MEF2C, and TOX proteins were decreased with miR-223 overexpression, while miR-223 inhibition led to increased protein levels in CTCL. In addition, we showed the 3′-UTR of TOX mRNA was a genuine target of miR-223. Therefore, reduced levels of miR-223 in MF/CTCL lead to increased expression of E2F1, MEF2C, and TOX, which likely contribute to the development and/or progression of CTCL. Thus, miR-223 and its targets may be useful for the development of new therapeutics for MF/CTCL.