CCL2/CCR2 axis induces hepatocellular carcinoma invasion and epithelial-mesenchymal transition in�vitro through activation of the Hedgehog pathway

Abstract

Chemokine (C-C motif) ligand 2 (CCL2) has been shown to play an important role in the regulation of tumor cell growth, metastasis and host immune response. CCL2 preferentially binds to the C-C chemokine receptor type 2 (CCR2), which is expressed in various tissues. However, the role of the CCL2/CCR2 axis in hepatocellular carcinoma (HCC) invasion and its molecular mechanisms remain unclear. The aim of this study was to elucidate this issue. The human HCC cell line MHCC-97H was treated with CCL2. Cyclopamine, a smoothened (SMO) antagonist, was used to inhibit SMO activity. CCR2 siRNA and Gli-1 siRNA were used to inhibit CCR2 and Gli-1 expression respectively. The effect of CCL2 and Hedgehog (Hh) signaling on cancer cell epithelial-mesenchymal transition (EMT) and invasion was evaluated by quantitative real-time PCR analysis, western blotting and Transwell invasion assay. Our results revealed that CCL2 induced HCC cell invasion and EMT. This effect was accompanied by the activation of Hh signaling, the upregulation of Snail and vimentin and the reduction of E-cadherin. Notably, prior silencing of CCR2 with siRNA abolished CCL2-induced Hh signaling activation, Snail and vimentin upregulation, E-cadherin reduction, as well as HCC cell invasion and EMT. Furthermore, pretreatment with cyclopamine or predepletion of Gli-1 by siRNA also eliminated the changes of Snail, vimentin and E-cadherin, and HCC invasion and EMT caused by CCL2. Collectively, our results revealed that the link between the CCL2/CCR2 axis and the Hh pathway plays an important role in HCC progression. Therefore, the CCL2/CCR2 axis may represent a promising therapeutic target to prevent HCC progression.

PLEK2 promotes gallbladder cancer invasion and metastasis through EGFR/CCL2 pathway

“…All these results suggested that PLEK2 regulated CCL2 expression through EGFR/STAT3 signaling. Previous studies indicated CCL2 induced EMT process mainly through the activation of transcription factor Snail [44, 45], but in our study, excretive CCL2 protein could partially rescue the inhibitory effects of PLEK2 knockdown by increasing Twist1 and ZEB1 expressions.…”

KSHV dysregulates bulk macroautophagy, mitophagy and UPR to promote endothelial to mesenchymal transition and CCL2 release, key events in viral‐driven sarcomagenesis

“…We further evaluated whether PERK activation could contribute to EndMT, which CCL2 has been reported to promote. 33 As shown in Figure 5B, GSK reduced SNAI1 expression, suggesting that UPR activation promoted sarcomagenesis by increasing the release of CCL2 and promoting 34 that both activates 35 and is activated by MTOR. 36 We show for the first time that MTOR activation correlated with bulk macroautophagy and mitophagy dysregulation and that such effects play an important role in KSHV-driven sarcomagenesis.…”

Identification of Therapeutic Targets and Prognostic Biomarkers Among CXC Chemokines in the Renal Cell Carcinoma Microenvironment

“…As expected, we found that the functions of these genes are primarily related to the chemokine signaling pathway, cytokine-cytokine receptor interactions, and the ILK signaling pathway. Previous studies have demonstrated that chemokine signaling pathways play key roles in the proliferation, senescence, angiogenesis, epithelialmesenchymal transition, immune evasion, and metastasis of various cancers (36)(37)(38)(39)(40). ILK, an ankyrin, repeat-containing serine/threonine protein kinase, plays a significant role in biological processes associated with tumorigenesis, including cancer cell proliferation, angiogenesis, metastasis, and drug resistance (41).…”