MicroRNA replacement therapy for miR-145 and miR-33a is efficacious in a model of colon carcinoma

MicroRNAs control the expression of various genes, and several miRNAs are aberrantly expressed in tumors. MiRNA-145 is markedly downregulated in various cancers including colon carcinoma, and in vitro studies have established its pro-apoptotic and anti-proliferative role. MiR-33a has only recently been connected to cancer through its capacity to downregulate the oncogenic kinase Pim-1. Despite the functional relevance of miRNAs suppressed in tumors, only a few studies have explored their therapeutic application. This miRNA replacement therapy is largely hampered by the lack of powerful non-viral delivery tools for their in vivo administration. In this paper, we establish, for the first time, miRNA replacement therapy by polyethylenimine (PEI)-mediated delivery of unmodified miRNAs. After systemic or local application of low molecular weight PEI/miRNA complexes, intact miRNA molecules are delivered into tumors, resulting in profound anti-tumor effects in s.c. colon carcinoma xenograft mouse models. Tumor inhibition is based on miR-145-mediated reduced proliferation, increased apoptosis and the concomitant repression of c-Myc and ERK5, which we identify for the first time as being regulated by miR-145. Furthermore, we introduce the systemic injection of PEI-complexed miR-33a as a novel therapeutic principle aiming at the in vivo downregulation of the oncogenic kinase Pim-1. Anti-tumor effects of the treatment with PEI/miRNA complexes are comparable to PEI/siRNA-mediated Pim-1 knockdown in vivo. Taken together, this is the first study to establish chemically unmodified miRNAs, complexed with PEI, as an efficient and biocompatible strategy for miRNA replacement therapy, and to introduce PEI/miR-145 and PEI/miR-33a complexes as anti-tumor compounds in colon carcinoma.