主催: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
会議名: WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
開催地: Kyoto
開催日: 2018/07/01 - 2018/07/06
Background: Both chemokine receptors (CXCR) 7 and 4 are known to be involved in a vast array of pathological events in the development cancer. However, it is not yet known whether the CXCR7/CXCR4 heterodimer can form in vivo, and if it does, the functional difference between CXCR7 monomer and the CXCR7/CXCR4 heterodimer.
Methods: The expression of two CXCRs, CXCR7/CXCR4 heterodimer and histone demethylase JMJD2A in human colorectal rectal cancer (CRC) tissue was detected by western blot and immunohistochemistry. We then studied the role of the CXCR7/CXCR4 heterodimer in CRC tumorigenesis in Villin-CXCR7-CXCR4 transgenic mice and APCMin/+/villin-CXCR7-CXCR4 mice.
Results: CXCR 7 and 4 can form heterodimers in vivo and promote colorectal tumorigenesis through histone demethylation. Compared with adjacent non-neoplastic tissue, human colorectal rectal cancer (CRC) tissue showed a significantly higher expression of CXCR4 and CXCR7, which was co-localized in the cancer cell epithelium. CXCR/CXCR4 heterodimerization was associated with increased histone demethylase JMJD2A. Villin-CXCR7-CXCR4 transgenic mice presented a greater degree of exacerbated colitis and tumorigenesis than villin-CXCR7 and villin-CXCR4 mice. The CXCR7/CXCR4 heterodimer also increased APC mutation-driven colorectal tumorigenesis in APCMin/+/villin-CXCR7-CXCR4 mice. Further analysis showed that the CXCR7/CXCR4 heterodimer induced nuclear b-arrestin 1 recruitment and histone demethylase JMJD2A, leading to histone demethylation and increased transcription of inflammatory factors and oncogenes.
Conclusions: Our data reveal a novel mechanism of colorectal tumorigenesis through CXCR7/CXCR4 heterodimer-induced histone demethylation. Inhibition of CXCR7/CXCR4 heterodimer-induced histone demethylation could be an effective strategy for cancer treatment (Figure).