MicroRNA Replacement Therapy for miR-145 and miR-33a Is Efficacious in a Model of Colon Carcinoma

Abstract

MicroRNAs (miRNA) aberrantly expressed in tumors may offer novel therapeutic approaches to treatment. miR-145 is downregulated in various cancers including colon carcinoma in which in vitro studies have established proapoptotic and antiproliferative roles. miR-33a was connected recently to cancer through its capacity to downregulate the oncogenic kinase Pim-1. To date, miRNA replacement therapy has been hampered by the lack of robust nonviral delivery methods for in vivo administration. Here we report a method of miRNA delivery by using polyethylenimine (PEI)-mediated delivery of unmodified miRNAs, using miR-145 and miR-33a to preclinically validate the method in a mouse model of colon carcinoma. After systemic or local application of low molecular weight PEI/miRNA complexes, intact miRNA molecules were delivered into mouse xenograft tumors, where they caused profound antitumor effects. miR-145 delivery reduced tumor proliferation and increased apoptosis, with concomitant repression of c-Myc and ERK5 as novel regulatory target of miR-145. Similarly, systemic injection of PEI-complexed miR-33a was validated as a novel therapeutic targeting method for Pim-1, with antitumor effects comparable with PEI/siRNA-mediated direct in vivo knockdown of Pim-1 in the model. Our findings show that chemically unmodified miRNAs complexed with PEI can be used in an efficient and biocompatible strategy of miRNA replacement therapy, as illustrated by efficacious delivery of PEI/miR-145 and PEI/miR-33a complexes in colon carcinoma. Cancer Res; 71(15); 5214-24. Ó2011 AACR.

Cholesterol lowering: role in cancer prevention and treatment

“…Recently, a number of miRNAs were found to be aberrantly expressed in cancer cells, and to play a role in regulating cancer progression (Huang and He, 2011). An intronic miRNA located within the gene encoding sterol-regulatory element-binding factor-2 (SREBF-2), miR-33, regulates cholesterol metabolism in concert with SREBPs, contributing to tumor growth Ibrahim et al, 2011), suggesting a therapeutic potential for miRNA modulation.…”

Silencing of ribonucleotide reductase subunit M1 potentiates the antitumor activity of gemcitabine in resistant cancer cells

“…23,24 Moreover, it was shown that PEI can also efficiently deliver siRNA complexed with it to tumors in mice after systemic administration. 25, 26 We therefore chose to employ PEI as a carrier for RRM1-specific siRNA in this study.…”

Low miR-145 silenced by DNA methylation promotes NSCLC cell proliferation, migration and invasion by targeting mucin 1

“…3 Emerging evidence has shown that miRNAs are involved in cancer initiation and progression. 4 MiR-145 has been reported as an important tumor suppressor gene in ovarian carcinoma, 5,6,7 malignant pleural mesothelioma, 8 breast cancer, 9 pancreatic cancer, 10,11 liposarcoma, 12 colorectal cancer, 13,14,15,16 neuroblastoma, 17 breast cancer, 18,19,20,21 esophageal cancer, 22 bladder cancer, 23,24 urothelial cancer, 25 prostate cancer, 26,27 gastric cancer, 28 and head and neck cancer, 29 and other types. MiR-145 was also implicated in the progression of NSCLC; 30,31,32 however, its exact mechanism is not well established.…”