Overexpression of CXCR4 synergizes with LL-37 in the metastasis of breast cancer cells |
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Authors: | Wen Liang Pan Yan Wang Yuan Hao Jack Ho Wong Wing Cheong Chan David Chi-Cheong Wan Tzi Bun Ng |
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Institution: | 1. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region;2. Department of Surgery, North District Hospital, Sheung Shui, New Territories, Hong Kong Special Administrative Region;3. Center for Translation Medicine Research and Development, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, The Chinese Academy of Sciences, Shenzhen, China |
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Abstract: | Chemokine receptor CXCR4 was involved in the progression of breast cancer to a metastatic phenotype, leading to the major cause of death in patients. A more in-depth understanding of signaling mechanism underlying CXCR4 is critical to develop effective therapies toward metastasis. Recently, the role of antimicrobial peptide LL-37 in contributing to the metastasis of breast cancer cells was observed. Clinical analysis of data herein demonstrated for the first time that overexpression of LL-37 and CXCR4 co-existed in human primary breast tumors with lymph node metastases. Further study disclosed that forced expression of CXCR4 led to the enhancement of pro-migratory signaling and migration rate induced by LL-37 in breast cancer cells. Moreover, LL-37 affected tumor microenvironment including induction of migration of mesenchymal stem cells and CXCR4-dependent capillary-like tubule formation. Functional analysis showed that LL-37 induced the internalization of CXCR4 through approaching Glu268, the residue of CXCR4, independent of the binding pocket (Asp171, Asp262, and Glu288) for CXCR4 inhibitor AMD3100, signifying that LL-37 is a distinct agonist of CXCR4. These results suggest the reciprocal roles of LL-37 and CXCR4 in promoting breast cancer cell migration and provide new insight into the design of CXCR4 inhibitor for intervention of metastatic breast cancer. |
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Keywords: | CXCR4 LL-37 Breast cancer Metastasis Epithelial-mesenchymal transition |
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