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CCR3 blockage elicits polyploidization associated with the signatures of epithelial-mesenchymal transition in carcinoma cell lines

Abstract

Malignant features such as the acquisition of metastatic ability, stemness of cells, and therapeutic resistance of cancer cells are associated with epithelial-mesenchymal transition (EMT) accompanied by changes in motility and morphology. Recent reports implicated that the formation of polyploid giant cancer cells (PGCCs) in human malignancy correlated with the EMT processes. Chemokines are often involved in the regulation of cancer cell migration into tissues, and various types of human cancers exhibit enhanced expression of chemokine receptors, which could augment intrinsic potentials such as invasive activity, proliferating ability, and survival capacity in cancer cells. Nevertheless, the contribution of CCR3 in malignant cancer cells is controversial because it is a well-known primal receptor for the migration of eosinophils, one of the cells of the innate immune system. Here, we explored the blockage of chemokine receptor CCR3 in carcinoma cell lines and found that inhibition of CCR3 induced the formation of polyploid giant cells and stabilization of β-catenin via the PI3K/Akt/GSK-3β signaling pathway, which are processes associated with EMT. As a result of CCR3 inhibition, converted cells acquired enhanced mobile and proliferation abilities. In summary, these data indicate that modulation of the CCR3/PI3K/Akt/GSK-3β signaling pathway regulates polyploidization associated with the EMT processes.

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Fig. 1: Treatment of CoCl2 and TGF-β induces the morphological change and reduction of CCR3 expression.
Fig. 2: Inhibition of CCR3 has similar potential to the treatment of CoCl2 and TGF-β in forming polyploid giant cells.
Fig. 3: Inhibition of CCR3 affects the generation of cells with DNA damages and aberrant centrosomes.
Fig. 4: Inhibition of CCR3 accumulates β-catenin via activation of the Akt/GSK-3β pathway and induces EMT signatures.
Fig. 5: CCL7 attenuates the effect of polyploidization and induction of EMT by CCR3 inhibition.
Fig. 6: Knock out of the CCR3 gene in Caco-2 cells induces the formation of polyploid giant cells and the EMT signatures via the PI3K/Akt/GSK-3β/β-catenin signaling pathway.
Fig. 7: Inhibition of CCR3 enhances migratory and proliferative activities of cancer cells.
Fig. 8: Inhibition of CCR3 leads to the polyploidization and EMT induced by the accumulation of β-catenin via the Akt/GSK-3β pathway.

Data availability

All the data generated and analyzed during this study are included in the published article and its supplementary information. The data supporting the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the JSPS (Japan Society for the Promotion of Science) KAKENHI [Grant Numbers 20K07456 and 21K15336].

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Y.K. and D.N. conceived and designed experiments. Y.K. carried out experiments. Y.K. and D.N. analyzed data and wrote the manuscript.

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Correspondence to Daisuke Nagakubo.

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Kaibori, Y., Nagakubo, D. CCR3 blockage elicits polyploidization associated with the signatures of epithelial-mesenchymal transition in carcinoma cell lines. Cancer Gene Ther (2022). https://doi.org/10.1038/s41417-022-00532-8

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