CC chemokine receptor-like 1 functions as a tumour suppressor by impairing CCR7-related chemotaxis in hepatocellular carcinoma

Jie Yi Shi, Liu Xiao Yang, Zhi Chao Wang, Ling Yan Wang, Jian Zhou, Xiao Ying Wang, Guo Ming Shi, Zhen Bin Ding, Ai Wu Ke, Zhi Dai, Shuang Jian Qiu, Qi Qun Tang, Qiang Gao, Jia Fan

Research output: Contribution to journalArticlepeer-review

Abstract

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-GSK3. pathway activation and nuclear accumulation of.-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.

Original languageEnglish (US)
Pages (from-to)546-558
Number of pages13
JournalJournal of Pathology
Volume235
Issue number4
DOIs
StatePublished - Mar 1 2015
Externally publishedYes

Keywords

  • Atypical chemokine receptor
  • Chemokine scavenger
  • Prognosis
  • Tumour microenvironment
  • β-catenin

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medicine(all)

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