Genistein inhibits stemness of SKOV3 cells induced by macrophages co-cultured with ovarian cancer stem-like cells through IL-8/STAT3 axis

Journal of Experimental & Clinical Cancer Research. 2019;38(1):1-15 DOI 10.1186/s13046-018-1010-1

 

Journal Homepage

Journal Title: Journal of Experimental & Clinical Cancer Research

ISSN: 1756-9966 (Online)

Publisher: BMC

Society/Institution: Regina Elena National Cancer Institute

LCC Subject Category: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens

Country of publisher: United Kingdom

Language of fulltext: English

Full-text formats available: PDF, HTML

 

AUTHORS


Yingxia Ning (Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Guangzhou Medical University)

Weifeng Feng (The First Affiliated Hospital of Jinan University)

Xiaocheng Cao (Department of Pharmaceutical Science, Medical College, Hunan Normal University)

Kaiqun Ren (Department of Pharmaceutical Science, Medical College, Hunan Normal University)

Meifang Quan (Department of Pharmaceutical Science, Medical College, Hunan Normal University)

A. Chen (Department of Pharmaceutical Science, Medical College, Hunan Normal University)

Chang Xu (Department of Pharmaceutical Science, Medical College, Hunan Normal University)

Yebei Qiu (Department of Pharmaceutical Science, Medical College, Hunan Normal University)

Jianguo Cao (Department of Pharmaceutical Science, Medical College, Hunan Normal University)

Xiang Li (Department of preclinical medicine, Medical College, Hunan Normal University)

Xin Luo (The First Affiliated Hospital of Jinan University)

EDITORIAL INFORMATION

Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 8 weeks

 

Abstract | Full Text

Abstract 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 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 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 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.