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- 학술저널
- 저자정보
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- 2017.1
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The chemokine CXCL10 and its receptor CXCR3 play a role in breast cancer metastasis to bone and osteoclast activation. However, the mechanism of CXCL10/CXCR3-induced intracellular signaling has not been fully investigated. To evaluate CXCL10-induced cellular events in the mouse breast cancer cell line 4T1, we developed a new synthetic CXCR3 antagonist JN-2. In this study, we observed that secretion of CXCL10 in the supernatant of 4T1 cells was gradually increased during cell growth. JN-2 inhibited basal and CXCL10-induced CXCL10 expression and cell motility in 4T1 cells. Treatment of 4T1 cells with CXCL10 increased the expression of P65, a subunit of the NF-κB pathway, via activation of the NF-κB transcriptional activity. Ectopic overexpression of P65 increased CXCL10 secretion and blunted JN-2-induced suppression of CXCL10 secretion, whereas overexpression of IκBα suppressed CXCL10 secretion. These results indicate that the CXCL10/CXCR3 axis creates a positive feedback loop through the canonical NF-κB signaling pathway in 4T1 cells. In addition, treatment of osteoblasts with conditioned medium from JN-2-treated 4T1 cells inhibited the expression of RANKL, a crucial cytokine for osteoclast differentiation, which resulted in an inhibitory effect on osteoclast differentiation in the co-culture system of bone marrowderived macrophages and osteoblasts. Direct intrafemoral injection of 4T1 cells induced severe bone destruction; however, this effect was suppressed by the CXCR3 antagonist via downregulation of P65 expression in an animal model. Collectively, these results suggest that the CXCL10/CXCR3-mediated NF-κB signaling pathway plays a role in the control of autonomous regulation of CXCL10 and malignant tumor properties in breast cancer 4T1 cells.
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참고문헌 (28)
참고문헌 신청
Akhtari M / 2008 / Biology of breast cancer bone metastasis / Cancer Biol Ther 7 : 3 ~ 9
Baggiolini M / 1998 / Chemokines and leukocyte traffic / Nature 392 : 565 ~ 568
Balkwill F / 2001 / Inflammation and cancer : back to Virchow? / Lancet 357 : 539 ~ 545
Balkwill F / 2004 / Cancer and the chemokine network / Nat Rev Cancer 4 : 540 ~ 550
Chen YC / 2010 / Breast cancer metastasis to the bone : mechanisms of bone loss / Breast Cancer Res 12 : 215 ~
Baggiolini M / 1998 / Chemokines and leukocyte traffic / Nature 392 : 565 ~ 568
Balkwill F / 2001 / Inflammation and cancer : back to Virchow? / Lancet 357 : 539 ~ 545
Balkwill F / 2004 / Cancer and the chemokine network / Nat Rev Cancer 4 : 540 ~ 550
Chen YC / 2010 / Breast cancer metastasis to the bone : mechanisms of bone loss / Breast Cancer Res 12 : 215 ~
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