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F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous manner
Kanae Yumimoto, … , Koshi Mimori, Keiichi I. Nakayama
Kanae Yumimoto, … , Koshi Mimori, Keiichi I. Nakayama
Published January 2, 2015
Citation Information: J Clin Invest. 2015;125(2):621-635. https://doi.org/10.1172/JCI78782.
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Research Article Oncology Article has an altmetric score of 24

F-box protein FBXW7 inhibits cancer metastasis in a non-cell-autonomous manner

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Abstract

The gene encoding F-box protein FBXW7 is frequently mutated in many human cancers. Although most previous studies have focused on the tumor-suppressive capacity of FBXW7 in tumor cells themselves, we determined that FBXW7 in the host microenvironment also suppresses cancer metastasis. Deletion of Fbxw7 in murine BM-derived stromal cells induced accumulation of NOTCH and consequent transcriptional activation of Ccl2. FBXW7-deficient mice exhibited increased serum levels of the chemokine CCL2, which resulted in the recruitment of both monocytic myeloid-derived suppressor cells and macrophages, thereby promoting metastatic tumor growth. Administration of a CCL2 receptor antagonist blocked the enhancement of metastasis in FBXW7-deficient mice. Furthermore, in human breast cancer patients, FBXW7 expression in peripheral blood was associated with serum CCL2 concentration and disease prognosis. Together, these results suggest that FBXW7 antagonizes cancer development in not only a cell-autonomous manner, but also a non-cell-autonomous manner, and that modulation of the FBXW7/NOTCH/CCL2 axis may provide a potential approach to suppression of cancer metastasis.

Authors

Kanae Yumimoto, Sayuri Akiyoshi, Hiroki Ueo, Yasuaki Sagara, Ichiro Onoyama, Hiroaki Ueo, Shinji Ohno, Masaki Mori, Koshi Mimori, Keiichi I. Nakayama

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Figure 6

NOTCH accumulation in FBXW7-deficient BMSCs promotes CCL2 expression and cancer metastasis.

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NOTCH accumulation in FBXW7-deficient BMSCs promotes CCL2 expression and...
(A) Immunoblot analysis of FBXW7 substrates in the indicated BMSCs. (B) Relative abundance of Ccl2 mRNA in WT BMSCs infected with retroviruses encoding NICD1, c-MYC, or KLF5. (C) Luciferase assay for the Ccl2 gene in BMSCs infected with retroviruses for NICD1, c-MYC, or KLF5. (D) Relative abundance of Ccl2 mRNA in CAG-Cre-ERT2 Fbxw7Δ/Δ BMSCs incubated with DAPT. (E) WT and mutant forms of the mouse Ccl2 gene promoter fused to the firefly luciferase gene. Consensus binding sequences for NOTCH–RBP-Jκ are shown in bold. Proximal and distal amplicons in G are indicated. (F) Luciferase assay for the Ccl2 gene in CAG-Cre-ERT2 Fbxw7Δ/Δ BMSCs. (G) ChIP analysis of the Ccl2 gene promoter. Immunoprecipitation was performed with antibodies against NOTCH1 or with control IgG. (H and I) Intravenous transplantation with B16F10 cells for Fbxw7fl/fl (n = 8), Fbxw7fl/fl RbpJκfl/fl (n = 11), Mx1-Cre Fbxw7Δ/Δ (n = 5), and Mx1-Cre Fbxw7Δ/Δ RbpJκΔ/Δ (n = 8) mice. (J and K) Intravenous transplantation with B16F10 cells for Fbxw7fl/fl (n = 8), Fbxw7fl/fl c-Mycfl/fl (n = 7), Mx1-Cre Fbxw7Δ/Δ (n = 6), and Mx1-Cre Fbxw7Δ/Δ c-MycΔ/Δ (n = 8) mice. Gross appearance of the lungs (H and J) and their occupancy by B16F10 colonies (I and K) are shown. (L) Serum concentration of CCL2, determined by ELISA. Scale bars: 10 mm (H and J). Data are mean ± SD (n = 3) (B–D, F, G, and L); horizontal bars in I and K indicate means. **P < 0.01, ***P < 0.001, 1-way ANOVA and Bonferroni test (B–D, I, K, and L).

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