Sphingosine-1-Phosphate–Cathelicidin Axis Plays a Pivotal Role in the Development of Cutaneous Squamous Cell Carcinoma

[Display omitted] Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer caused by mutagenesis resulting from excess UVR or other types of oxidative stress. These stressors also upregulate the production of a cutaneous innate immune element, cathelicidin antimicrobial peptide (CAMP), throu...

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Veröffentlicht in:Journal of investigative dermatology 2024-08
Hauptverfasser: Park, Kyungho, Shin, Kyong-Oh, Kim, Young-Il, Nielsen-Scott, Anna L., Mainzer, Carine, Celli, Anna, Bae, Yoojin, Chae, Seungwoo, An, Hahyun, Choi, Yerim, Park, Jae-Ho, Park, Soo-Hyun, Hwang, Jin-Taek, Kang, Seung Goo, Wakefield, Joan S., Arron, Sarah T., Holleran, Walter M., Mauro, Theodora M., Elias, Peter M., Uchida, Yoshikazu
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Sprache:eng
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Zusammenfassung:[Display omitted] Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer caused by mutagenesis resulting from excess UVR or other types of oxidative stress. These stressors also upregulate the production of a cutaneous innate immune element, cathelicidin antimicrobial peptide (CAMP), through endoplasmic reticulum stress–initiated, sphingosine-1-phosphate (S1P) signaling pathway. Although CAMP has beneficial antimicrobial activities, it also can be proinflammatory and procarcinogenic. We addressed whether and how S1P-induced CAMP production leads to cSCC development. Our study demonstrated that (i) CAMP expression is increased in cSCC cells and skin from patients with cSCC; (ii) S1P levels are elevated in cSCC cells, whereas inhibition of S1P production attenuates CAMP-stimulated cSCC growth; (iii) exogenous CAMP stimulates cSCC but not normal human keratinocyte growth; (iv) blockade of FPRL1 protein, a CAMP receptor, attenuates cSCC growth as well as the growth and invasion of cSCC cells mediated by CAMP into an extracellular matrix–containing fibroblast substrate; (v) FOXP3+ regulatory T-cell (which decreases antitumor immunity) levels increase in cSCC skin; and (vi) CAMP induces endoplasmic reticulum stress in cSCC cells. Together, the endoplasmic reticulum stress–S1P–CAMP axis forms a vicious circle, creating a favorable environment for cSCC development, that is, cSCC growth and invasion impede anticancer immunity.
ISSN:0022-202X
1523-1747
1523-1747
DOI:10.1016/j.jid.2024.08.008