MicroRNAs and their therapeutic potential for human diseases: microRNAs, miR-143 and -145, function as anti-oncomirs and the application of chemically modified miR-143 as an anti-cancer drug.
We examined the expression levels of microRNAs (miRNAs; miRs) in colorectal tumors (63 cancer specimens and 65 adenoma specimens) compared to adjacent non-tumorous tissues. Decreased expression of miR-143 and -145 was frequently observed in the adenoma and cancer samples. As the down-regulation of miR-143 and -145 was observed even in the early phase of adenoma formation, their decreased expression would appear to contribute mainly to the initiation of tumorigenesis. For clinical application, we added aromatic benzene-pyridine (BP-type) analogs to the 3'-overhang region of the RNA-strand and changed the sequences of the passenger strand in the miR-143 duplex (miR-143BPs), leading to greater activity and increased resistance to nuclease. The cell growth inhibitory effect of the chemically modified miR-143BPx in vitro was greater than that of the endogenous miR-143. The modified miR-143BPx showed a significant tumor-suppressive effect on xenografted tumors of human colorectal cancer DLD-1 cells. These findings suggest that miR-143 and -145 are important onco-related genes for the initiation of colorectal tumor development and that chemically modified miR-143BPx may be a candidate for an RNA medicine for the treatment of colorectal tumors.
United Graduate School of Drug Discovery and Medicinal Information Sciences, Gifu University, Japan. ykkitade@gifu-u.ac.jp
Yukio
Y
Kitade
Yukihiro
Y
Akao
D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003106:Colon / Q000503:physiopathology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D006131:Growth Inhibitors; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; C542359:MIRN143 microRNA, human; C541010:MIRN145 microRNA, human; D035683:MicroRNAs