Clinical relevance and therapeutic significance of microRNA-133a expression profiles and functions in malignant osteosarcoma-initiating cells.
Novel strategies against treatment-resistant tumor cells remain a challenging but promising therapeutic approach. Despite accumulated evidence suggesting the presence of highly malignant cell populations within tumors, the unsolved issues such as in vivo targeting and clinical relevance remain. Here, we report a preclinical trial based on the identified molecular mechanisms underlying osteosarcoma-initiating cells and their clinical relevance. We identified key microRNAs (miRNAs) that were deregulated in a highly malignant CD133(high) population and found that miR-133a regulated the cell invasion that characterizes a lethal tumor phenotype. Silencing of miR-133a with locked nucleic acid (LNA) reduced cell invasion of this cell population, and systemic administration of LNA along with chemotherapy suppressed lung metastasis and prolonged the survival of osteosarcoma-bearing mice. Furthermore, in a clinical study, high expression levels of CD133 and miR-133a were significantly correlated with poor prognosis, whereas high expression levels of the four miR-133a target genes were correlated with good prognosis. Overall, silencing of miR-133a with concurrent chemotherapy would represent a novel strategy that targets multiple regulatory pathways associated with metastasis of the malignant cell population within osteosarcoma.
Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan; Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
Tomohiro
T
Fujiwara
Takeshi
T
Katsuda
Keitaro
K
Hagiwara
Nobuyoshi
N
Kosaka
Yusuke
Y
Yoshioka
Ryou-U
RU
Takahashi
Fumitaka
F
Takeshita
Daisuke
D
Kubota
Tadashi
T
Kondo
Hitoshi
H
Ichikawa
Akihiko
A
Yoshida
Eisuke
E
Kobayashi
Akira
A
Kawai
Toshifumi
T
Ozaki
Takahiro
T
Ochiya
D000071916:AC133 Antigen; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001859:Bone Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000556:secondary / Q000628:therapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D035683:MicroRNAs / Q000096:biosynthesis*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy; D010455:Peptides / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis*; D015996:Survival Rate
D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C548234:MIRN133 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D012334:RNA, Neoplasm
Clinical translation; Locked nucleic acid; MicroRNA; Osteosarcoma