Deficiency of C-C chemokine receptor 5 suppresses tumor development via inactivation of NF-κB and inhibition of monocyte chemoattractant protein-1 in urethane-induced lung tumor model Article

Lee, NJ, Choi, DY, Song, JK et al. (2012). Deficiency of C-C chemokine receptor 5 suppresses tumor development via inactivation of NF-κB and inhibition of monocyte chemoattractant protein-1 in urethane-induced lung tumor model . CARCINOGENESIS, 33(12), 2520-2528. 10.1093/carcin/bgs265

cited authors

  • Lee, NJ; Choi, DY; Song, JK; Jung, YY; Kim, DH; Kim, TM; Kim, DJ; Kwon, SM; Kim, KB; Choi, KE; Moon, DC; Kim, Y; Han, SB; Hong, JT

authors

abstract

  • To evaluate the significance of C-C chemokine receptor type 5 (CCR5) in lung tumor development, we compared carcinogen-induced tumor growth in CCR5 knockout (CCR5. -/-) mice and wild-type (CCR5. +/+) mice. CCR5. -/- mice showed reduced urethane (1g/kg)-induced tumor incidence when compared with those of CCR5. +/+ mice. We investigated the activation of nuclear factor-kappaB/STAT3 since these are implicated transcription factors in the regulation of genes involving tumor growth. Significant inhibition of DNA-binding activity of nuclear factor-kappaB and STAT3, and the translocation of p50 and p65 into the nucleus and the phosphorylation of IκB were found in the lungs of CCR5. -/- mice compared with the lungs of CCR5. +/+ mice. Expression of apoptotic protein such as cleaved caspase-3, cleaved PARP and Bax was elevated, whereas the expression levels of survival protein such as Bcl-2 and cIAP1 was decreased in the lungs of CCR5. -/- mice. Interestingly, we found that the level of monocyte chemoattractant protein-1 (MCP-1), a tumor growth-promoting cytokine, was significantly reduced in the lung tumor tissue and blood of CCR5. -/- mice compared with the level in CCR5. +/+ mice. In addition, CCR5 small interfering RNA (siRNA) and inhibitor of MCP-1 blocked lung cancer cell growth, which was abolished by the addition of MCP-1 protein in cultured lung cancer cells. Moreover, inactivation of CD8. + cytotoxic T cell and dendritic cells was significantly increased in the blood, lung tumors and spleens of CCR5. -/- mice compared with that of CCR5. +/+ mice. Therefore, these results showed that CCR5 deficiency suppressed lung tumor development through the inhibition of nuclear factor-kappaB/STAT3 pathways and the downregulation of MCP-1 in the carcinogen-induced lung tumor model. © The Author 2012. Published by Oxford University Press. All rights reserved.

publication date

  • December 1, 2012

published in

Digital Object Identifier (DOI)

start page

  • 2520

end page

  • 2528

volume

  • 33

issue

  • 12