Skip to main content
ARS Home » Northeast Area » Beltsville, Maryland (BHNRC) » Beltsville Human Nutrition Research Center » Diet, Genomics and Immunology Laboratory » Research » Publications at this Location » Publication #359085
Title: Modulation of CXC-motif chemokine receptor 7, but not 4 expression, is related to migration of the human prostate cancer cell LNCaP: regulation by androgen and inflammatory stimuli

Author
item YU, LU - University Of Maryland
item Pham, Quynhchi
item YU, LIANGLI - University Of Maryland
item Wang, Thomas - Tom

Submitted to: Inflammation Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/5/2019
Publication Date: 12/21/2019
Citation: Yu, L., Pham, Q., Yu, L., Wang, T.T. 2019. Modulation of CXC-motif chemokine receptor 7, but not 4 expression, is related to migration of the human prostate cancer cell LNCaP: regulation by androgen and inflammatory stimuli. Inflammation Research. 69, 167-178. https://doi.org/10.1007/s00011-019-01305-0.
DOI: https://doi.org/10.1007/s00011-019-01305-0

Interpretive Summary: Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in U.S. men. Tumor microenvironment is thought to be critical for prostate cancer (PCa) development. Cross talk between inflammatory pathways and androgen action contribute to the complexity of tumor microenvironment, but detailed mechanisms remain unclear. The present study examined the regulation of the metastasis-related chemokine CXC-motif ligand 12 (CXCL12) and its CXC-motif receptor (CXCR) 4 and 7 by androgen and Toll-like receptor 5 (TLR5) in prostate cancer cells. We found that the treatment of the androgen-responsive LNCaP cells with dihydrotestosterone (DHT) and the TLR5 ligand, flagellin, increased CXCR4 mRNA but decreased CXCR7 mRNA levels. Silencing androgen receptor (AR) using AR siRNA significantly attenuated the effects of DHT on CXCR7 and CXCR4 mRNA. Interestingly, at the protein level, we only observed a decrease in CXCR7 but no change in CXCR4 by DHT and flagellin. We also found that both DHT and flagellin treatment, which decrease CXCR7 protein, synergistically increased the migration of LNCaP cells towards CXCL12. In summary, androgen, TLR5 and CXCR chemokine pathway cross-talk exists. At the molecular level, only CXCR7 was regulated by androgen and TLR5 at both transcriptional and translational levels, indicating a disconnect in the CXCR4 regulation at the transcriptional and translational levels. The changes in CXCR7 protein correlated with the increased migration of LNCaP cells stimulated by DHT and flagellin, supporting the hypothesis that CXCR7 may play a role as a decoy receptor in prostate cancer cell migration and counteract CXCL12/CXCR4 migration promoting effects. Hence, androgen as well as inflammation may promote prostate cancer cell migration/metastasis through the regulation of CXCR7. This study provides novel information on regulatory mechanisms of immune responses in prostate cancer development and will benefit basic and translational scientists who are studying the regulation of the prostate cancer tumor microenvironment.

Technical Abstract: Tumor microenvironment is thought to be critical for prostate cancer (PCa) development. Cross talk between inflammatory pathways and androgen action contributes to the complexity of the tumor microenvironment, but detailed mechanisms remain unclear. The present study examined the regulation of the metastasis-related chemokine CXC-motif ligand 12 (CXCL12) and its CXC-motif receptor (CXCR) 4 and 7 by androgen and Toll-like receptor 5 (TLR5) in prostate cancer cells. We found that the treatment of the androgen-responsive LNCaP cells with dihydrotestosterone (DHT) and the TLR5 ligand, flagellin, increased CXCR4 mRNA, but decreased CXCR7 mRNA levels. Silencing the androgen receptor (AR) using AR siRNA significantly attenuated the effects of DHT on CXCR7 and CXCR4 mRNA. Interestingly, at the protein level, we only observed a decrease in CXCR7 but no change in CXCR4 by DHT and flagellin. We also found that both DHT and flagellin treatment, which decrease CXCR7 protein, synergistically increased the migration of LNCaP cells towards CXCL12. In summary, androgen, TLR5 and CXCR chemokine pathway cross-talk exists. At the molecular level, only CXCR7 was regulated by androgen and TLR5 at both transcriptional and translational levels, indicating a disconnect in the CXCR4 regulation at the transcriptional and translational level. The changes in CXCR7 protein correlated with an increased migration of LNCaP cells stimulated by DHT and flagellin, supporting the hypothesis that CXCR7 may play a role as a decoy receptor in prostate cancer cell migration and counteract CXCL12/CXCR4 migration promoting effects. Hence, androgen as well as inflammation may promote prostate cancer cell migration/metastasis through the regulation of CXCR7.