Abstract
Metastasis of liver cancer is closely linked to tumor microenvironment, in which chemokines and their receptors act in an important role. The CXCR3, the receptor of chemokine CXCL9, belongs to a superfamily of rhodopsin-like seven transmembrane GPCRs and CXCR subfamily. In HCC tissues, CXCR3 was frequently upregulated and correlated with tumor size, tumor differentiation, portal invasion and metastasis. In the study, CXCR3-A isoform that was bound by CXCL9 was found to cause significant change of ERK1/2 phosphorylation level in the MAPK signaling pathway, consequently upregulating the MMP2 and MMP9 expression and promoting invasion and metastasis of CD133+ liver cancer cells. Also, CXCR3-A suppressed the adhesion ability of CD133+ liver cancer cells that stimulated by CXCL9 for 24h. These findings suggest that CXCR3 and its ligand CXCL9 could promote the metastasis of liver cancer cells and might be a potential target for the intervention of liver cancer metastasis.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer, and it is the third most common cancer leading to the death worldwide [1]
We focused on the chemokine receptor CXCR3 and its ligand CXCL9
CXCR3, which belong to the G protein-coupled seven transmembrane family of receptors(GPCR), is involved in some signaling pathways such as PI3K and MAPK [28, 29], and these pathways play a key role in tumor development [30, 31]
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer, and it is the third most common cancer leading to the death worldwide [1]. Emerging evidence indicates that tumor microenvironment is significant in metastasis and invasion of tumor cells, in which chemokines are a vital constituent part [5]. Previous research in our laboratory suggested that HBV protein X (HBx) can activate nuclear factor-kappa B (NF-kB), subsequently upregulating the chemokine CXCL9 expression [8]. CXCR3, a G-protein coupled receptor of chemokine CXCL9, is significant in tumor progression and angiogenesis, and has been found to be correlated with poor prognosis for breast tumors, melanoma, and colon and renal cancer patients [12]. The CXCR3-alt isoform is still able to mediate CXCL11- but not CXCL9or CXCL10-dependent activity [13]. The role and molecular mechanism of chemokine CXCL9 with CXCR3 receptor isoforms in the metastasis and development of HCC has not been reported
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