Cyclin-dependent kinase 9 (CDK9) is a novel prognostic marker and therapeutic target in osteosarcoma.
Adolescent
Adult
Aged
Biomarkers, Tumor
/ metabolism
Bone Neoplasms
/ metabolism
Cell Culture Techniques
Cell Line, Tumor
Cell Movement
Cell Proliferation
Child
Cyclin-Dependent Kinase 9
/ metabolism
Early Detection of Cancer
Female
Gene Expression Regulation, Neoplastic
Humans
Male
Middle Aged
Osteosarcoma
/ metabolism
Phosphorylation
Prognosis
RNA Polymerase II
/ metabolism
Survival Analysis
Tissue Array Analysis
Up-Regulation
Young Adult
Apoptosis
CDK9
Osteosarcoma
Prognostic marker
Therapeutic target
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Jan 2019
Jan 2019
Historique:
received:
03
08
2018
revised:
07
12
2018
accepted:
12
12
2018
pubmed:
24
12
2018
medline:
14
6
2019
entrez:
24
12
2018
Statut:
ppublish
Résumé
Cyclin-dependent protein kinase 9 (CDK9) has been shown to play an important role in the pathogenesis of malignant tumors. However, the expression and function of CDK9 remain unknown in osteosarcomas. The purpose of this study is to assess the expression, function and clinical prognostic relationship of CDK9 in osteosarcomas. A tissue microarray of 70 patient specimens was analyzed by immunohistochemistry to measure CDK9 expression, which was further investigated for correlation with patient clinical characteristics. CDK9 expression in osteosarcoma cell lines and patient tissues was also evaluated by Western blotting. CDK9-specific siRNA and the CDK9 inhibitor were applied to determine the effect of CDK9 inhibition on osteosarcoma cell proliferation and anti-apoptotic activity. The clonogenicity and migration activity were also examined using clonogenic and wound healing assays. A 3D cell culture model was performed to mimic the in vivo osteosarcoma environment to further validate the effect of CDK9 inhibition on osteosarcoma cells. We demonstrated that higher CDK9-expression is associated with significantly shortened patient survival by immunohistochemistry. Expression of CDK9 is inversely correlated to the percent of tumor necrosis post-neoadjuvant chemotherapy, which is the most important predictive factor of disease outcome for osteosarcoma patients. Knockdown of CDK9 with siRNA and inhibition of CDK9 activity with inhibitor decreased cell proliferation and induced apoptosis in osteosarcoma. High expression of CDK9 is an independent predictor of poor prognosis in osteosarcoma patients. Our results suggest that CDK9 is a novel prognostic marker and a promising therapeutic target for osteosarcomas.
Sections du résumé
BACKGROUND
BACKGROUND
Cyclin-dependent protein kinase 9 (CDK9) has been shown to play an important role in the pathogenesis of malignant tumors. However, the expression and function of CDK9 remain unknown in osteosarcomas. The purpose of this study is to assess the expression, function and clinical prognostic relationship of CDK9 in osteosarcomas.
METHODS
METHODS
A tissue microarray of 70 patient specimens was analyzed by immunohistochemistry to measure CDK9 expression, which was further investigated for correlation with patient clinical characteristics. CDK9 expression in osteosarcoma cell lines and patient tissues was also evaluated by Western blotting. CDK9-specific siRNA and the CDK9 inhibitor were applied to determine the effect of CDK9 inhibition on osteosarcoma cell proliferation and anti-apoptotic activity. The clonogenicity and migration activity were also examined using clonogenic and wound healing assays. A 3D cell culture model was performed to mimic the in vivo osteosarcoma environment to further validate the effect of CDK9 inhibition on osteosarcoma cells.
FINDINGS
RESULTS
We demonstrated that higher CDK9-expression is associated with significantly shortened patient survival by immunohistochemistry. Expression of CDK9 is inversely correlated to the percent of tumor necrosis post-neoadjuvant chemotherapy, which is the most important predictive factor of disease outcome for osteosarcoma patients. Knockdown of CDK9 with siRNA and inhibition of CDK9 activity with inhibitor decreased cell proliferation and induced apoptosis in osteosarcoma.
INTERPRETATION
CONCLUSIONS
High expression of CDK9 is an independent predictor of poor prognosis in osteosarcoma patients. Our results suggest that CDK9 is a novel prognostic marker and a promising therapeutic target for osteosarcomas.
Identifiants
pubmed: 30579871
pii: S2352-3964(18)30599-1
doi: 10.1016/j.ebiom.2018.12.022
pmc: PMC6355967
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
CDK9 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 9
EC 2.7.11.22
RNA Polymerase II
EC 2.7.7.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
182-193Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
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