Journal Article

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

Nam Jin Lee, Dong Young Choi, Ju Kyoung Song, Yu Yeon Jung, Dae Han Kim, Tae Myung Kim, Dae Joong Kim, Sun Mi Kwon, Kyung Bo Kim, Kyung Eun Choi, Dong Cheul Moon, Youngsoo Kim, Sang Bae Han and Jin Tae Hong

in Carcinogenesis

Volume 33, issue 12, pages 2520-2528
Published in print December 2012 | ISSN: 0143-3334
Published online August 2012 | e-ISSN: 1460-2180 | DOI:

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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 IĸB 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.

Journal Article.  6900 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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