deficiency of c-c chemokine receptor 5 suppresses tumor development via inactivation of nf-κb and upregulation of il-1ra in melanoma model缺乏碳碳趋化因子受体5抑制肿瘤的发展通过失活nf-κb和il-1ra upregulation黑色素瘤模型.pdfVIP

Deficiency of C-C Chemokine Receptor 5 Suppresses Tumor Development via Inactivation of NF-kB and Upregulation of IL-1Ra in Melanoma Model 1 1 1 1 1 2 Ju Kyoung Song , Mi Hee Park , Dong-Young Choi , Hwan Soo Yoo , Sang Bae Han , Do Young Yoon , Jin Tae Hong1* 1 College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea, 2 Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul, Republic of Korea Abstract To evaluate the relevance of C-C chemokine receptor type 5 (CCR5) expression and tumor development, we compared melanoma growth in CCR5 knockout (CCR52/ 2) mice and wild type (CCR5+/+) mice. CCR52/ 2 mice showed reduced tumor volume, tumor weight, and increased survival rate when compared to CCR5+/+ mice. We investigated the activation of NF- kB since it is an implicated transcription factor in the regulation of genes involving cell growth, apoptosis, and tumor growth. Significant inhibition of DNA binding activity of NF-kB, and translocation of p50 and p65 into the nucleus through the inhibition of phosphorylation of IkB was found in the melanoma tissues of CCR52/ 2 mice compared to melanoma tissues of CCR5+/+ mice. NF-kB target apoptotic protein expression, such as cleaved caspase-3, cleaved PARP, and Bax, was elevated, whereas the survival protein expression levels, such as Bcl-2, C-IAP1, was decreased in the melanoma tissues of CCR52/ 2 mice. Interestingly, we found that the level of IL-1Ra, a tumor growth suppressive cytokine, was significantly elevated in tumor tissue and spleen of CCR52/ 2 mice compared to the level in CCR5+/+ mice. Moreover,