Construction of a CXCL12-KDEL fusion gene to inhibit head and neck squamous cell carcinoma metastasis by intracellular sequestration of CXCR4.

Abstract

The CXCL12-CXCR4 biological axis consisting of the chemotactic factor CXCL12 and its specific receptor CXCR4 plays an important role in oral cancer metastasis. High expression of CXCR4 may help oral squamous cancer cells invade local tissues and metastasize to lymph nodes. No obvious association was observed between CXCL12 expression and lymph node metastasis, suggesting that CXCL12 chemotaxis may only be related to CXCR4 expression on the tumor cell membrane. KDEL can be retained by receptors on the surface of the intracellular endoplasmic reticulum (ER) and also be called an ER retention signal sequence. So we adopted the KDEL sequence in this study to generate a CXCL12-KDEL fusion protein in combination with a traceable E-tag label. As such, CXCL12 was retained in the ER. Specific receptor CXCR4 binds to the CXCL12-KDEL, was also retained in the ER, and was thus prevented from reaching the oral squamous cancer cell surface. We reduced the cell surface level of CXCR4 and called the technique “intracellular sequestration.” By this way, we have finished blocking of CXCL12-CXCR4 biological axis and inhibiting lymph node metastasis of oral carcinoma.