The CCL21/CCR7 pathway plays a key role in human colon cancer metastasis through regulation of matrix metalloproteinase-9

Abstract 

Purpose

CC chemokine receptor 7 (CCR7) and matrix metalloproteinase-9 (MMP-9) have been associated with lymph node metastasis in human colon cancer. Studies have suggested a potential link between CCR7 and MMP-9 in cancer; however, the molecular mechanism by which C–C ligand 21/CCR7 promotes tumour dissemination in human colon cancer is not well understood. Thus, we aimed to determine whether MMP-9 is regulated by the C–C ligand 21/CCR7 in human colon cancer.

Method

RNA interference technology was employed to detect effect of CCR7 deficiency on the expression of MMP-9 in SW480 human colon cancer cells. We also evaluated the ability of CCR7 short hairpin RNA to inhibit MMP-9 production and tumour invasion in a xenografted mouse model by using whole-body fluorescence imaging and gelatin zymography.

Result

We found that CCR7 short hairpin RNA significantly inhibited C–C ligand 21/CCR7-induced up-regulation of MMP-9 in SW480 cells. Furthermore, knockdown of CCR7 significantly limited the production of MMP-9 and colon cancer metastasis in a xenografted mouse model. Mice that received SW480/control cells had progressively enlarging tumours and more lymphatic metastases, and these animals did not survive as long as mice that received SW480/CCR7⁻ cells.

Conclusion

MMP-9 and CCR7 may be useful targets for the treatment of lymphatic metastasis in colon cancer.

Abbreviations: MMP-9, matrix metalloproteinase-9, CCR7, CC chemokine receptor 7, ECM, extracellular matrix, CCL21, C–C ligand 21

Keywords: Matrix metalloproteinase-9, CC chemokine receptor 7, Whole-body fluorescence imaging, Colon cancer metastasis