Iron accelerates Fusobacterium nucleatum–induced CCL8 expression in macrophages and is associated with colorectal cancer progression
Taishi Yamane, … , Hideo Baba, Toshiro Moroishi
Taishi Yamane, … , Hideo Baba, Toshiro Moroishi
Published September 22, 2022
Citation Information: JCI Insight. 2022;7(21):e156802. https://doi.org/10.1172/jci.insight.156802.
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Research Article Oncology

Iron accelerates Fusobacterium nucleatum–induced CCL8 expression in macrophages and is associated with colorectal cancer progression

Abstract

Accumulating evidence suggests that high levels of Fusobacterium nucleatum in colorectal tumor tissues can be associated with poor prognosis in patients with colorectal cancer (CRC); however, data regarding distinct prognostic subgroups in F. nucleatum–positive CRC remain limited. Herein, we demonstrate that high-iron status was associated with a worse prognosis in patients with CRC with F. nucleatum. Patients with CRC presenting elevated serum transferrin saturation exhibited preferential iron deposition in macrophages in the tumor microenvironment. In addition, F. nucleatum induced CCL8 expression in macrophages via the TLR4/NF-κB signaling pathway, which was inhibited by iron deficiency. Mechanistically, iron attenuated the inhibitory phosphorylation of NF-κB p65 by activating serine/threonine phosphatases, augmenting tumor-promoting chemokine production in macrophages. Our observations indicate a key role for iron in modulating the NF-κB signaling pathway and suggest its prognostic potential as a determining factor for interpatient heterogeneity in F. nucleatum–positive CRC.

Authors

Taishi Yamane, Yohei Kanamori, Hiroshi Sawayama, Hiromu Yano, Akihiro Nita, Yudai Ohta, Hironori Hinokuma, Ayato Maeda, Akiko Iwai, Takashi Matsumoto, Mayuko Shimoda, Mayumi Niimura, Shingo Usuki, Noriko Yasuda-Yoshihara, Masato Niwa, Yoshifumi Baba, Takatsugu Ishimoto, Yoshihiro Komohara, Tomohiro Sawa, Tasuku Hirayama, Hideo Baba, Toshiro Moroishi

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Figure 4

Iron negatively regulates S536 phosphorylation of NF-κB p65, thereby accelerating activation of TLR4/NF-κB signaling.

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Iron negatively regulates S536 phosphorylation of NF-κB p65, thereby acc...
(A) Iron is required for LPS-induced chemokine expression in THP-1 macrophages. THP-1 cells were pretreated with ferric ammonium citrate (FAC; 100 μM) and/or deferoxamine (DFO; 100 μM) for 8 hours, followed by treatment with LPS (100 ng/mL) for 3 hours. RT-qPCR analysis of chemokine expression is shown. Data are presented as the mean ± SD of triplicates from a representative experiment. n.d., not detected. (B) Iron chelation does not affect LPS-induced phosphorylation and degradation of IκB. THP-1 cells were pretreated with DFO (100 μM) for 8 hours, followed by treatment with LPS (100 ng/mL) for the indicated times. Immunoblot analysis of phospho-IκB and total IκB is shown. (C) Iron deletion does not affect LPS-induced nuclear translocation of NF-κB p65. THP-1 cells were pretreated with DFO (100 μM) for 8 hours, followed by treatment with LPS (100 ng/mL) for the indicated times. Immunofluorescence staining for NF-κB p65 is shown. N, nuclear; C, cytoplasmic. Scale bar: 20 μm. (D) Iron deficiency enhances the inhibitory phosphorylation of NF-κB p65 at S536. THP-1 cells were treated with DFO (100 μM) for 8 hours prior to LPS (100 ng/mL) treatment for the indicated time, followed by immunoblot analysis.