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

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-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.

Protein tyrosine phosphatase PTP4A1 promotes proliferation and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma via the PI3K/AKT pathway

“…Immunohistochemistry for PTP4A1 was performed using a two-step protocol as previously described [32]. Briefly, paraffin sections were baked for 30min at 70°C, de-paraffinized in xylene, rehydrated in gradually varied alcohol, and then the sections were managed with 1% H 2 O 2 to neutralize endogenous peroxidase for 30min.…”

“…For real-time RT-PCR, SYBR Premix Ex Taq™ (Takara, Japan) was used according to the manufacturer's instructions as previously described [32]. Primers were designed as follows: PTP4A1, forward: 5′-ACCAATGCGACCTTAAACAAA-3′and reverse: 5′-AATCTGGTTGGATGGTGGTG-3′; GAPDH, forward: 5′-AGCCACATCGCTCAGACAC-3′and reverse: 5′-GAATTTGCCATGGGTGGA-3′.…”

Therapeutic Lymphoid Organogenesis in the Tumor Microenvironment

“…However, CCR7 has also been reported to have detrimental effects in certain cancers. In hepatocellular carcinoma, signaling by both CCL19 and CCL21 promoted the proliferation and invasion of tumor cells, while CCRL1/CCX-CKR, a naturally occurring receptor sink for the CCR7 ligands, was able to mitigate these effects (Shi et al, 2015). CCRL1 is unable to induce intrinsic intracellular signaling pathways, but it mediates the internalization and degradation of CCL19 and disallows its agonism of CCR7 (Comerford, Milasta, Morrow, Milligan, & Nibbs, 2006).…”

Atypical chemokine receptors in cancer: friends or foes?

“…Supporting the protective role of ACKR4 in tumor growth and dissemination, there are data from human breast [91], hepatocellular [92], and colon [93] cancer samples in which downregulation of ACKR4 is correlated with a worse outcome.…”

“…Few results have been published about the role of ACKR4 in cancer biology. Overexpression of ACKR4 inhibited the in vitro proliferation of breast cancer cell lines MDA-MB-425 and MDA-MB-231 [91] and hepatocellular carcinoma cell lines MHCC97L and HCCLM3 [92]. In vivo, beside inhibition of tumor growth, there is also reduced metastasis with concomitant decreased levels of ACKR4 ligands.…”