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

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 15; pp. 5214 - 5224
• Main Authors: AHMED FAWZY IBRAHIM, WEIRAUCH, Ulrike, THOMAS, Maren, GRÜNWELLER, Arnold, HARTMANN, Roland K, AIGNER, Achim
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-08-2011
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adenocarcinoma - therapy; Animal models; Animals; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Colonic Neoplasms - therapy; Drug Carriers; Drug Delivery Systems; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Genetic Therapy; Humans; Medical sciences; Mice; Mice, Nude; MicroRNAs - administration & dosage; MicroRNAs - genetics; MicroRNAs - therapeutic use; Mitogen-Activated Protein Kinase 7 - biosynthesis; Mitogen-Activated Protein Kinase 7 - genetics; Molecular Weight; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Pharmacology. Drug treatments; Polyethyleneimine - administration & dosage; Proto-Oncogene Proteins c-myc - biosynthesis; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors; Proto-Oncogene Proteins c-pim-1 - genetics; Random Allocation; RNA, Small Interfering - pharmacology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Xenograft Model Antitumor Assays; Colonic disease; Gene silencing; Replacement therapy; Colon cancer; RNA interference; Micro RNA; Digestive diseases; Intestinal disease; Models; Malignant tumor; Colon carcinoma; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-4645

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.