Musashi2 contributes to the maintenance of CD44v6+ liver cancer stem cells via notch1 signaling pathway.
Animals
Body Integrity Identity Disorder
Carcinoma, Hepatocellular
/ etiology
Cell Line, Tumor
Disease Models, Animal
Fluorescent Antibody Technique
Gene Expression
Gene Knockdown Techniques
Humans
Hyaluronan Receptors
/ genetics
Immunohistochemistry
Liver Neoplasms
/ etiology
Male
Mice
Models, Biological
Neoplastic Stem Cells
/ metabolism
Prognosis
RNA-Binding Proteins
/ genetics
Receptor, Notch1
/ metabolism
Signal Transduction
CD44 variant exon 6
Hepatocellular carcinoma
Liver cancer stem cells
Musashi2
Notch1 signaling pathway
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
30 Dec 2019
30 Dec 2019
Historique:
received:
01
10
2019
accepted:
16
12
2019
entrez:
1
1
2020
pubmed:
1
1
2020
medline:
16
5
2020
Statut:
epublish
Résumé
Liver cancer stem cells (LCSCs) contribute to hepatocellular carcinoma (HCC) development, metastasis, and drug resistance. MSI2 and Notch1 signaling are involved in the maintenance of CSCs. However, it is unknown whether MSI2 and Notch1 are involved in the maintenance of CD44v6+ LCSCs. Therefore, we investigated the clinical significance and function of MSI2 and its relationship with Notch1 signaling in the maintenance of stemness properties in CD44v6+ LCSCs. The expression of MSI2 and CD44v6 were detected by fresh specimens and a HCC tissue microarray. The tissue microarray containing 82 HCC samples was used to analyze the correlation between CD44v6 and MSI2. CD44v6+/- cells were isolated using microbeads sorting. We explored the roles of MSI2 and Notch1 signaling in CD44v6+ LCSCs by sphere formation assay, transwell assay, clone formation assay in vitro, and xenograft tumor models in vivo. A Notch RT Here, we found MSI2 expression was positively correlated with high CD44v6 expression in HCC tissues, and further correlated with tumor differentiation. CD44v6+ cells isolated from HCC cell lines exhibited increased self-renewal, proliferation, migration and invasion, resistance to Sorafenib and tumorigenic capacity. Both MSI2 and Notch1 signaling were elevated in sorted CD44v6+ cells than CD44v6- cells and played essential roles in the maintenance of stemness of CD44v6+ LCSCs. Mechanically, MSI2 directly bound to Lunatic fringe (LFNG) mRNA and protein, resulting in Notch1 activation. Our results demonstrated that MSI2 maintained the stemness of CD44v6+ LCSCs by activating Notch1 signaling through the interaction with LFNG, which could be a potential molecular target for stem cell-targeted therapy for liver cancer.
Sections du résumé
BACKGROUND
BACKGROUND
Liver cancer stem cells (LCSCs) contribute to hepatocellular carcinoma (HCC) development, metastasis, and drug resistance. MSI2 and Notch1 signaling are involved in the maintenance of CSCs. However, it is unknown whether MSI2 and Notch1 are involved in the maintenance of CD44v6+ LCSCs. Therefore, we investigated the clinical significance and function of MSI2 and its relationship with Notch1 signaling in the maintenance of stemness properties in CD44v6+ LCSCs.
METHODS
METHODS
The expression of MSI2 and CD44v6 were detected by fresh specimens and a HCC tissue microarray. The tissue microarray containing 82 HCC samples was used to analyze the correlation between CD44v6 and MSI2. CD44v6+/- cells were isolated using microbeads sorting. We explored the roles of MSI2 and Notch1 signaling in CD44v6+ LCSCs by sphere formation assay, transwell assay, clone formation assay in vitro, and xenograft tumor models in vivo. A Notch RT
RESULTS
RESULTS
Here, we found MSI2 expression was positively correlated with high CD44v6 expression in HCC tissues, and further correlated with tumor differentiation. CD44v6+ cells isolated from HCC cell lines exhibited increased self-renewal, proliferation, migration and invasion, resistance to Sorafenib and tumorigenic capacity. Both MSI2 and Notch1 signaling were elevated in sorted CD44v6+ cells than CD44v6- cells and played essential roles in the maintenance of stemness of CD44v6+ LCSCs. Mechanically, MSI2 directly bound to Lunatic fringe (LFNG) mRNA and protein, resulting in Notch1 activation.
CONCLUSIONS
CONCLUSIONS
Our results demonstrated that MSI2 maintained the stemness of CD44v6+ LCSCs by activating Notch1 signaling through the interaction with LFNG, which could be a potential molecular target for stem cell-targeted therapy for liver cancer.
Identifiants
pubmed: 31888685
doi: 10.1186/s13046-019-1508-1
pii: 10.1186/s13046-019-1508-1
pmc: PMC6936093
doi:
Substances chimiques
CD44v6 antigen
0
Hyaluronan Receptors
0
MSI2 protein, human
0
NOTCH1 protein, human
0
RNA-Binding Proteins
0
Receptor, Notch1
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
505Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK120531
Pays : United States
Organisme : National Natural Science Foundation of China
ID : 81802418
Organisme : National Natural Science Foundation of China
ID : 81172063, 81372352
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