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Cancer Sci. 2018 Mar;109(3):710-723. doi: 10.1111/cas.13487. Epub 2018 Feb 13.

C-C chemokine receptor type 1 mediates osteopontin-promoted metastasis in hepatocellular carcinoma.

Zhu Y1,2,3, Gao XM1,2,3, Yang J1,2,3, Xu D1,2,3, Zhang Y1,2,3, Lu M1,2,3, Zhang Z1,2,3, Sheng YY1,2,3, Li JH1,2,3, Yu XX1,2,3, Zheng Y1,2,3, Dong QZ1,2,3, Qin LX1,2,3.

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Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China.
Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Institutes of Cancer Metastasis, Fudan University, Shanghai, China.


In the hepatocellular carcinoma (HCC) microenvironment, chemokine receptors play a critical role in tumorigenesis and metastasis. Our previous studies have found that osteopontin (OPN) is a promoter for HCC metastasis. However, the role of chemokine receptors in OPN-induced HCC metastasis remains unclear. In this study, we demonstrate that OPN is dramatically elevated in HCC tissues with metastasis and that high expression of OPN correlates with poorer overall survival and higher recurrence rate. OPN upregulates chemokine receptor expression, migration, invasion and pulmonary metastasis in HCC. We find that C-C chemokine receptor type 1 (CCR1) and C-X-C chemokine receptor type 6 (CXCR6) are the most upregulated chemokine receptors induced by OPN. CCR1 knockdown results in reduction of migration, invasion and pulmonary metastasis induced by OPN in vitro and in vivo, whereas CXCR6 knockdown does not reverse OPN-promoted migration and invasion. Moreover, OPN upregulates the expression of CCR1 through activating phosphoinositide 3-kinase (PI3K)/AKT and hypoxia-inducible factor 1α (HIF-1α) in HCC cells. Furthermore, blockade of OPN-CCR1 axis with CCR1 antagonist significantly restrains the promoting effects of OPN on HCC progression and metastasis. In human HCC tissues, OPN expression shows significantly positive correlation with CCR1 expression, and the patients with high levels of both OPN and CCR1 have the most dismal prognosis. Collectively, our results indicate that the OPN-CCR1 axis in HCC is important for accelerating tumor metastasis and that CCR1 is a potential therapeutic target for controlling metastasis in HCC patients with high OPN.


BX471; CCR1; hepatocellular carcinoma; metastasis; osteopontin

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