Shi Jie-Yi, Yang Liu-Xiao, Wang Zhi-Chao, Wang Ling-Yan, Zhou Jian, Wang Xiao-Ying, Shi Guo-Ming, Ding Zhen-Bin, Ke Ai-Wu, Dai Zhi, Qiu Shuang-Jian, Tang Qi-Qun, Gao Qiang, Fan Jia
Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, People's Republic of China.
J Pathol. 2015 Mar;235(4):546-58. doi: 10.1002/path.4450. Epub 2014 Dec 18.
Atypical chemokine receptors (ACRs) have been discovered to participate in the regulation of tumour behaviour. Here we report a tumour-suppressive role of a novel ACR member, CC chemokine receptor like 1 (CCRL1), in human hepatocellular carcinoma (HCC). Both mRNA and protein expressions of CCRL1 correlated with the malignant phenotype of HCC cells and were significantly down-regulated in tumour tissue compared with paired normal liver tissue. In both the initial and validation cohorts (n = 240 and n = 384, respectively), CCRL1 deficiency was associated with advanced tumour stage and was an independent index for worse survival and increased recurrence. Furthermore, knock-down or forced expression of CCRL1 revealed that CCRL1 suppressed the proliferation and invasion of HCC cells in vitro and reduced tumour growth and lung metastasis in vivo, with depressed levels of CCL19 and CCL21. By sequestrating CCL19 and CCL21, CCRL1 reduced their binding to CCR7 and consequently mitigated the detrimental impact of CCR7, including Akt-GSK3β pathway activation and nuclear accumulation of β-catenin in tumour cells. Clinically, the prognostic value of the CCR7 expression in HCC depended on the expression level of CCRL1, suggesting that CCRL1 may serve as an upstream switch for the CCR7 signalling cascade. Together, our findings suggest that CCRL1 impairs chemotactic events associated with CCR7 in the progression and metastasis of HCC. Our results also show a potential interplay between typical and atypical chemokine receptors in human cancer. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
非典型趋化因子受体（ACRs）已被发现参与肿瘤行为的调控。在此，我们报告一种新型ACR成员，CC趋化因子受体样1（CCRL1）在人类肝细胞癌（HCC）中的肿瘤抑制作用。CCRL1的mRNA和蛋白表达均与HCC细胞的恶性表型相关，且与配对的正常肝组织相比，在肿瘤组织中显著下调。在初始队列和验证队列中（分别为n = 240和n = 384），CCRL1缺陷与肿瘤晚期相关，是生存率降低和复发增加的独立指标。此外，敲低或强制表达CCRL1显示，CCRL1在体外抑制HCC细胞的增殖和侵袭，在体内减少肿瘤生长和肺转移，同时CCL19和CCL21水平降低。通过隔离CCL19和CCL21，CCRL1减少它们与CCR7的结合，从而减轻CCR7的有害影响，包括肿瘤细胞中Akt - GSK3β途径的激活和β - 连环蛋白的核积累。临床上，HCC中CCR7表达的预后价值取决于CCRL1的表达水平，这表明CCRL1可能作为CCR7信号级联的上游开关。总之，我们的研究结果表明CCRL1在HCC的进展和转移中损害与CCR7相关的趋化事件。我们的结果还显示了人类癌症中典型和非典型趋化因子受体之间的潜在相互作用。版权所有© 2014英国及爱尔兰病理学会。由约翰·威利父子有限公司出版。
