Role of anti-oncomirs miR-143 and -145 in human colorectal tumors.
We examined the expression levels of microRNAs (miRNAs (miRs)) in colorectal tumors (63 cancer specimens and 65 adenoma specimens) and paired non-tumorous tissues. Decreased expression of miR-143 and -145 was frequently observed in the adenomas and cancers tested, compared with miR-34a downregulation and miR-21 upregulation. Expression profiles of miR-143 and -145 were not associated with any clinical features. As the downregulation of miR-143 and -145 was observed even in the early phase of adenoma formation, the decreased expression of both miRs would appear to contribute mainly to the initiation step of tumorigenesis, not to the progression stage, and not to clinical prognostic factors. For clinical application, we changed the sequences of the passenger strand in the miR-143 duplex and performed chemical modification at the 3'-overhang portion of miR-143, leading to greater activity and stability to nuclease. The cell growth inhibitory effect of the chemically modified synthetic miR-143 in vitro was greater than that of endogenous miR-143. The miR-143 showed a significant tumor-suppressive effect on xenografted tumors of DLD-1 human colorectal cancer cells. These findings suggest that miR-143 and -145 are important onco-related genes for the initiation step of colorectal tumor development and that the chemically modified synthetic miR-143 may be a hopeful candidate as an RNA medicine for the treatment of colorectal tumors.
Akao
Y
Y
Department of Medical Oncology, Gifu International Institute of Biotechnology, Kakamigahara, Gifu, Japan. yakao@giib.or.jp
Nakagawa
Y
Y
Hirata
I
I
Iio
A
A
Itoh
T
T
Kojima
K
K
Nakashima
R
R
Kitade
Y
Y
Naoe
T
T
D000236:Adenoma / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000235:genetics*; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
D035683:MicroRNAs; C542359:MIRN143 microRNA, human; C541010:MIRN145 microRNA, human; C524940:MIRN21 microRNA, human; C522425:MIRN34 microRNA, human; C549242:MIRN7-1 microRNA, human