MiR-26a inhibits stem cell-like phenotype and tumor growth of osteosarcoma by targeting Jagged1.
MicroRNAs (miRNAs) are important epigenetic regulators of gene expression. Although several miRNAs have been implicated in osteosarcoma, their role in regulation of osteosarcoma cancer stem cells (CSCs) remains unknown. Here we demonstrated that miR-26a is downregulated in osteosarcoma CSCs when derived by either sarcosphere generation, chemodrug or aldehyde dehydrogenase (ALDH) activity selection. Lentiviral overexpression of miR-26a in ZOS and 143B osteosarcoma cells decreases the expression of stem cell markers and suppresses sarcosphere formation, as well as ALDH activity. Moreover, miR-26a overexpression inhibits the tumor cell growth both in vitro and in vivo. We further demonstrate that miR-26a directly target Jagged1, one of the Notch ligand, and that its tumor suppressive effects are mediated through inhibition of Jagged1/Notch signaling. Importantly, reduced miR-26a expression, as determined by in situ hybridization in patient tumors (n=92), is associated with lung metastasis and poor overall survival of osteosarcoma patients. Together, these data suggest the essential role of miR-26a/Jagged1/Notch pathway in regulating the stem cell-like traits of osteosarcoma cells and provide a potential target for osteosarcoma therapy.
Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
J
J
Lu
Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
G
G
Song
Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Q
Q
Tang
Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
J
J
Yin
Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
C
C
Zou
Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Z
Z
Zhao
Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
X
X
Xie
Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
H
H
Xu
Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
G
G
Huang
Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
J
J
Wang
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA.
D-F
DF
Lee
Princess Margaret Cancer Centre/Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
R
R
Khokha
Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
H
H
Yang
Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
J
J
Shen
D020413:3' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000072100:Jagged-1 Protein / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology* / Q000556:secondary*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D015398:Signal Transduction; D016019:Survival Analysis; D055815:Young Adult
D020413:3' Untranslated Regions; D000072100:Jagged-1 Protein; D035683:MicroRNAs; C000606273:JAG1 protein, human; C528163:MIRN26 microRNA, human