LAUSR

ABSTRACT One of the major causes of death in colorectal cancer (CRC) is invasion and metastasis. Better understanding of the molecular mechanism of CRC invasion and metastasis is essential in developing effective cancer therapies. Cooperative effect of CXCR3 and CXCR4 plays a crucial role in regulating CRC invasion. In present study, we discovered that CRC cells expressing higher levels of CXCR3 and CXCR4 were more invasive. Additionally, CXCR3 formed heteromers with CXCR4 and retained CXCR4 on cell surface. CXCR3 knockdown reduced surface CXCR4 expression and partially inhibited CRC cell invasion. On the contrary, CXCR3 overexpression enhanced surface CXCR4 abundance and promoted CRC cell invasion. Further research indicated that CXCR3‐A isoform was responsible for increased CXCR4 surface expression and CRC cell invasion. However, CXCR3‐A overexpression without CXCR4 expression did not cause CRC cell invasion, which suggested that CXCR3‐A indirectly affect cell invasion through regulating CXCR4. Taken together, CXCR3 enhanced CXCR4 function in CRC cell invasion through forming heteromers with CXCR4 on cell surface and prevent CXCR4 internalization. Therefore, targeting CXCR3 could be a promising strategy for clinical treatment of CRC cell invasion and metastasis. HighlightsColon cancer cells with both CXCR3 and CXCR4 expression showed significantly stronger invasive phenotype.In CRC cells, CXCR3 prevented CXCR4 internalization through forming heteromers with CXCR4 on cell surface.CXCR3‐A, instead of CXCR3‐B, was mainly responsible for inhibited CXCR4 internalization and enhanced cell invasion.CRC cells with both CXCR3 and CXCR4 expression showed more metastasis in mice lung tissue after intravenously injections.