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. 2020 Nov;26(8):1668-1676.
doi: 10.1111/odi.13500. Epub 2020 Jun 30.

The chemokine lymphotactin and its recombinant variants in oral cancer cell regulation

Amir Zaki Abdullah Zubir  1 , Simon A Whawell  1 , Tuck Seng Wong  2 , Syed Ali Khurram  1
Affiliations
Free article

The chemokine lymphotactin and its recombinant variants in oral cancer cell regulation

Amir Zaki Abdullah Zubir et al. Oral Dis. 2020 Nov.
Free article

Abstract

Background: The expression of XCR1 receptor and its metamorphic ligand lymphotactin (hLtn) has been shown in cancers but their precise role in tumorigenesis is poorly understood including the significance of the physiologically existing hLtn monomeric (CC3) and dimeric (W55D) confirmations where the latter thought to function as the receptor antagonist. The aim of this study was to explore the functional role of bioengineered hLtn variants and the role of fibroblasts in XCR1/hLtn expression regulation in oral cancer cells (OCCL).

Material and methods: qRT-PCR and flow cytometry were performed to evaluate mRNA and protein expression of XCR1 and hLtn. Recombinant hLtn variants (wild-type, CC3 and W55D mutant) were designed, expressed, purified and evaluated using proliferation, adhesion and chemotaxis assays. XCR1 and hLtn expression regulation by fibroblasts was determined using indirect co-culture. XCR1 and hLtn expression in primary and metastatic OSCC tissue was assessed using immunohistochemistry.

Results: hLtn caused a significant decrease in OCCL XCR1 surface protein expression. hLtn CC3 mutant was highly functional facilitating proliferation and migration. Conditioned media from primary cancer-associated and senescent fibroblasts significantly upregulated XCR1 and hLtn mRNA expression in OCCL. Immunohistochemistry revealed higher XCR1 and hLtn expression in metastatic tumour deposits and surrounding stroma compared to primary OSCC tissue.

Conclusions: The development of hLtn biological mutants, regulation of XCR1 expression by its ligand hLtn and crosstalk with fibroblasts are novel findings suggesting an important role for the XCR1/hLtn axis within the OSCC tumour microenvironment. These discoveries build upon previous studies and suggest that the hLtn/XCR1 axis has a significant role in stromal crosstalk and OSCC progression.

Keywords: XCR1; cancer-associated fibroblast; lymphotactin; oral squamous cell carcinoma; tumour microenvironment.

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References

REFERENCES

    1. Bennett, L. D., Fox, J. M., & Signoret, N. (2011). Mechanisms regulating chemokine receptor activity. Immunology, 134(3), 246-256. https://doi.org/10.1111/j.1365-2567.2011.03485.x
    1. Carulli, M. T., Ong, V. H., Ponticos, M., Shiwen, X. U., Abraham, D. J., Black, C. M., & Denton, C. P. (2005). Chemokine receptor CCR2 expression by systemic sclerosis fibroblasts: Evidence for autocrine regulation of myofibroblast differentiation. Arthritis and Rheumatism, 52(12), 3772-3782. https://doi.org/10.1002/art.21396
    1. Chen, K., Bao, Z., Tang, P., Gong, W., Yoshimura, T., & Wang, J. M. (2018). Chemokines in homeostasis and diseases. Cellular & Molecular Immunology, 15(4), 324-334. https://doi.org/10.1038/cmi.2017.134
    1. Chu, T.-Y., Yang, J.-T., Huang, T.-H., & Liu, H.-W. (2014). Crosstalk with cancer-associated fibroblasts increases the growth and radiation survival of cervical cancer cells. Radiation Research, 181(5), 540-547. https://doi.org/10.1667/RR13583.1
    1. Ding, S., Chen, G., Zhang, W. U., Xing, C., Xu, X., Xie, H., … Zhou, L. (2015). MRC-5 fibroblast-conditioned medium influences multiple pathways regulating invasion, migration, proliferation, and apoptosis in hepatocellular carcinoma. Journal of Translational Medicine, 13, 237. https://doi.org/10.1186/s12967-015-0588-8