Genistein inhibits stemness of SKOV3 cells induced by macrophages co-cultured with ovarian cancer stem-like cells through IL-8/STAT3 axis.
Animals
Cell Line, Tumor
Coculture Techniques
Disease Models, Animal
Female
Gene Expression
Genistein
/ pharmacology
Humans
Interleukin-8
/ metabolism
Macrophages
/ immunology
Mice
Neoplastic Stem Cells
/ drug effects
Ovarian Neoplasms
/ genetics
STAT3 Transcription Factor
/ genetics
Spheroids, Cellular
Tumor Cells, Cultured
Tumor Microenvironment
Tumor Stem Cell Assay
Genistein
IL-8/STAT3 axis
Ovarian cancer
Ovarian cancer stem-like cells
Tumor associated macrophages
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:
15 Jan 2019
15 Jan 2019
Historique:
received:
24
09
2018
accepted:
17
12
2018
entrez:
17
1
2019
pubmed:
17
1
2019
medline:
12
4
2019
Statut:
epublish
Résumé
Recent studies showed that macrophages co-cultured with ovarian cancer stem-like cells (OCSLCs) induced SKOV3 cell stemness via IL-8/STAT3 signaling. Genistein (GEN) demonstrates chemopreventive activity in inflammation-associated cancers. The present study aimed to examine whether and if GEN inhibits the stemness of SKOV3 and OVCA-3R cells induced by co-culture of THP-1 macrophages and SKOV3-derived OCSLCs. The co-culture was treated with or without different concentrations (10, 20, and 40 μmol/L) of GEN for 24 h. Depletion or addition of IL-8 in Co-CM and knockdown or overexpression of STAT3 in THP-1 macrophages was performed to demonstrate the possible associated mechanisms. The combined effects of GEN and STAT3 knockdown were examined with the nude mouse modle by co-injection of SKOV3-derived OCSLCs with THP-1 macrophages. Our results showed that GEN down-regulated CD163 and p-STAT3 expression of THP-1 macrophage, decreased the levels of IL-10, increased the levels of IL-12 and nitric oxide (NO) in the conditioned medium, and reduced the clonogenic and sphere-forming capacities and the expression of CD133 and CD44 in SKOV3 cells induced by co-culture of THP-1 macrophages and OCSLCs in a dose-dependent manner. Moreover, depletion or addition of IL-8 enhanced or attenuated the effect of GEN. Additionally, knockdown or overepression of STAT3 in THP-1 macrophages potentiated or attenuated the inhibitory effects of GEN. Importantly, STAT3 overexpression retrieved the effects of IL-8 combined with GEN depletion on M2 polarization of THP-1 macrophages and stemness of SKOV3 cells induced by co-culture. The combination of GEN and STAT3 knockdown cooperatively inhibited the growth of tumors co-inoculated with OCSLCs/THP-1 macrophages in nude mice in vivo through blocking IL-8/STAT3 signaling. In summary, our findings suggested that GEN can inhibit the increased M2 polarization of macrophages and stemness of ovarian cancer cells by co-culture of macrophages with OCSLCs through disrupting IL-8/STAT3 signaling axis. This assisted GEN to be as a potential chemotherapeutic agent in human ovarian cancer.
Sections du résumé
BACKGROUND
BACKGROUND
Recent studies showed that macrophages co-cultured with ovarian cancer stem-like cells (OCSLCs) induced SKOV3 cell stemness via IL-8/STAT3 signaling. Genistein (GEN) demonstrates chemopreventive activity in inflammation-associated cancers. The present study aimed to examine whether and if GEN inhibits the stemness of SKOV3 and OVCA-3R cells induced by co-culture of THP-1 macrophages and SKOV3-derived OCSLCs.
METHODS
METHODS
The co-culture was treated with or without different concentrations (10, 20, and 40 μmol/L) of GEN for 24 h. Depletion or addition of IL-8 in Co-CM and knockdown or overexpression of STAT3 in THP-1 macrophages was performed to demonstrate the possible associated mechanisms. The combined effects of GEN and STAT3 knockdown were examined with the nude mouse modle by co-injection of SKOV3-derived OCSLCs with THP-1 macrophages.
RESULTS
RESULTS
Our results showed that GEN down-regulated CD163 and p-STAT3 expression of THP-1 macrophage, decreased the levels of IL-10, increased the levels of IL-12 and nitric oxide (NO) in the conditioned medium, and reduced the clonogenic and sphere-forming capacities and the expression of CD133 and CD44 in SKOV3 cells induced by co-culture of THP-1 macrophages and OCSLCs in a dose-dependent manner. Moreover, depletion or addition of IL-8 enhanced or attenuated the effect of GEN. Additionally, knockdown or overepression of STAT3 in THP-1 macrophages potentiated or attenuated the inhibitory effects of GEN. Importantly, STAT3 overexpression retrieved the effects of IL-8 combined with GEN depletion on M2 polarization of THP-1 macrophages and stemness of SKOV3 cells induced by co-culture. The combination of GEN and STAT3 knockdown cooperatively inhibited the growth of tumors co-inoculated with OCSLCs/THP-1 macrophages in nude mice in vivo through blocking IL-8/STAT3 signaling.
CONCLUSIONS
CONCLUSIONS
In summary, our findings suggested that GEN can inhibit the increased M2 polarization of macrophages and stemness of ovarian cancer cells by co-culture of macrophages with OCSLCs through disrupting IL-8/STAT3 signaling axis. This assisted GEN to be as a potential chemotherapeutic agent in human ovarian cancer.
Identifiants
pubmed: 30646963
doi: 10.1186/s13046-018-1010-1
pii: 10.1186/s13046-018-1010-1
pmc: PMC6334437
doi:
Substances chimiques
Interleukin-8
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
Genistein
DH2M523P0H
Types de publication
Journal Article
Retracted Publication
Langues
eng
Sous-ensembles de citation
IM
Pagination
19Subventions
Organisme : National Natural Science Foundation of China
ID : 81301894, 81302249
Organisme : Guangzhou Science and Information Bureau Item
ID : No.201300000151
Organisme : Guangdong Province Department of Science and Technology
ID : No.2014A020211028, 2014A020212609, 2012B031800271
Organisme : the scientific research project for Medical College of Bureau of Education of Guangzhou City
ID : No.1201410508
Organisme : The High-Level Academic Talent Training Program of Guangzhou Medical University ([2017] 210)
ID : B185004083
Commentaires et corrections
Type : ErratumIn
Type : RetractionIn
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