Mechanism of chemoresistance mediated by miR-140 in human osteosarcoma and colon cancer cells.
In this study, high-throughput microRNA (miRNA) expression analysis revealed that the expression of miR-140 was associated with chemosensitivity in osteosarcoma tumor xenografts. Tumor cells ectopically transfected with miR-140 were more resistant to methotrexate and 5-fluorouracil (5-FU). Overexpression of miR-140 inhibited cell proliferation in both osteosarcoma U-2 OS (wt-p53) and colon cancer HCT 116 (wt-p53) cell lines, but less so in osteosarcoma MG63 (mut-p53) and colon cancer HCT 116 (null-p53) cell lines. miR-140 induced p53 and p21 expression accompanied with G(1) and G(2) phase arrest only in cell lines containing wild type of p53. Histone deacetylase 4 (HDAC4) was confirmed to be one of the important targets of miR-140. The expression of endogenous miR-140 was significantly elevated in CD133(+hi)CD44(+hi) colon cancer stem-like cells that exhibit slow proliferating rate and chemoresistance. Blocking endogenous miR-140 by locked nucleic acid-modified anti-miR partially sensitized resistant colon cancer stem-like cells to 5-FU treatment. Taken together, our findings indicate that miR-140 is involved in the chemoresistance by reduced cell proliferation through G(1) and G(2) phase arrest mediated in part through the suppression of HDAC4. miR-140 may be a candidate target to develop novel therapeutic strategy to overcome drug resistance.
Song
B
B
Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY 11794-8691, USA.
Wang
Y
Y
Xi
Y
Y
Kudo
K
K
Bruheim
S
S
Botchkina
G I
GI
Gavin
E
E
Wan
Y
Y
Formentini
A
A
Kornmann
M
M
Fodstad
O
O
Ju
J
J
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53 / Q000502:physiology; D045325:HCT116 Cells; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
D000964:Antimetabolites, Antineoplastic; D035683:MicroRNAs; C544302:Mirn140 microRNA, human; D005472:Fluorouracil; D008727:Methotrexate