Clinical relevance and therapeutic significance of microRNA-133a expression profiles and functions in malignant osteosarcoma-initiating cells.

Abstract

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.

• Authors: Tomohiro Fujiwara, Takeshi Katsuda, Keitaro Hagiwara, Nobuyoshi Kosaka, Yusuke Yoshioka, Ryou-U Takahashi, Fumitaka Takeshita, Daisuke Kubota, Tadashi Kondo, Hitoshi Ichikawa, Akihiko Yoshida, Eisuke Kobayashi, Akira Kawai, Toshifumi Ozaki, Takahiro Ochiya
• Journal: Stem cells (Dayton, Ohio) (Stem Cells) Vol. 32 Issue 4 Pg. 959-73 (Apr 2014) ISSN: 1549-4918 [Electronic] England
• PMID: 24715690 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 AlphaMed Press.

Chemical References

• AC133 Antigen
• Antigens, CD
• Glycoproteins
• MIRN133 microRNA, human
• MicroRNAs
• Neoplasm Proteins
• PROM1 protein, human
• Peptides
• Prom1 protein, mouse
• RNA, Neoplasm

Topics

• AC133 Antigen
• Adult
• Animals
• Antigens, CD (metabolism)
• Bone Neoplasms (metabolism, mortality, pathology, therapy)
• Disease-Free Survival
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Glycoproteins (metabolism)
• Humans
• Lung Neoplasms (metabolism, mortality, pathology, secondary, therapy)
• Male
• Mice
• Mice, Nude
• Mice, SCID
• MicroRNAs (biosynthesis)
• Neoplasm Invasiveness
• Neoplasm Proteins (metabolism)
• Osteosarcoma (metabolism, mortality, pathology, therapy)
• Peptides (metabolism)
• RNA, Neoplasm (biosynthesis)
• Survival Rate