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

Yingxia Ning ; Weifeng Feng ; Xiaocheng Cao ; Kaiqun Ren ; Meifang Quan ; A. Chen ; Chang Xu ; Yebei Qiu ; Jianguo Cao ; Xiang Li ; Xin Luo

Journal of Experimental & Clinical Cancer Research, 01 January 2019, Vol.38(1), pp.1-15 [Periódico revisado por pares]

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  • Título:
    Genistein inhibits stemness of SKOV3 cells induced by macrophages co-cultured with ovarian cancer stem-like cells through IL-8/STAT3 axis
  • Autor: Yingxia Ning ; Weifeng Feng ; Xiaocheng Cao ; Kaiqun Ren ; Meifang Quan ; A. Chen ; Chang Xu ; Yebei Qiu ; Jianguo Cao ; Xiang Li ; Xin Luo
  • Assuntos: Ovarian Cancer ; Tumor Associated Macrophages ; Ovarian Cancer Stem-Like Cells ; Genistein ; Il-8/Stat3 Axis ; Medicine
  • É parte de: Journal of Experimental & Clinical Cancer Research, 01 January 2019, Vol.38(1), pp.1-15
  • Descrição: 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. Electronic supplementary material The online version of this article (10.1186/s13046-018-1010-1) contains supplementary material, which is available to authorized users.
  • Idioma: Inglês

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