FGF19/FGFR4 signaling axis confines and switches the role of melatonin in head and neck cancer metastasis.

Autor: Lang L; Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA., Xiong Y; Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA.; Present address: Department of Otolaryngology Head and Neck Surgery, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China., Prieto-Dominguez N; Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA., Loveless R; Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA., Jensen C; Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA., Shay C; Department of Pediatrics, Emory Children's Center, Emory University, Atlanta, GA, USA., Teng Y; Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA. yteng@augusta.edu.; Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA. yteng@augusta.edu.; Department of Medical Laboratory, Imaging and Radiologic Sciences, College of Allied Health, Augusta University, Augusta, GA, USA. yteng@augusta.edu.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2021 Mar 10; Vol. 40 (1), pp. 93. Date of Electronic Publication: 2021 Mar 10.
DOI: 10.1186/s13046-021-01888-9
Abstrakt: Background: There is no consensus about the effective dosages of melatonin in cancer management, thus, it is imperative to fully understand the dose-dependent responsiveness of cancer cells to melatonin and the underlying mechanisms.
Methods: Head and neck squamous cell carcinoma (HNSCC) cells with or without melatonin treatment were used as a research platform. Gene depletion was achieved by short hairpin RNA, small interfering RNA, and CRISPR/Cas9. Molecular changes and regulations were assessed by Western blotting, quantitative RT-PCR (qRT-PCR), immunohistochemistry, and chromatin Immunoprecipitation coupled with qPCR (ChIP-qPCR). The therapeutic efficacy of FGF19/FGFR4 inhibition in melatonin-mediated tumor growth and metastasis was evaluated in orthotopic tongue tumor mice.
Results: The effect of melatonin on controlling cell motility and metastasis varies in HNSCC cells, which is dose-dependent. Mechanistically, high-dose melatonin facilitates the upregulation of FGF19 expression through activating endoplasmic stress (ER)-associated protein kinase RNA-like endoplasmic reticulum kinase (PERK)-Eukaryotic initiation factor 2 alpha (eIF2α)-activating transcription factor 4 (ATF4) pathway, which in turn promotes FGFR4-Vimentin invasive signaling and attenuates the role of melatonin in repressing metastasis. Intriguingly, following long-term exposure to high-dose melatonin, epithelial HNSCC cells revert the process towards mesenchymal transition and turn more aggressive, which is enabled by FGF19/FGFR4 upregulation and alleviated by genetic depletion of the FGF19 and FGFR4 genes or the treatment of FGFR4 inhibitor H3B-6527.
Conclusions: Our study gains novel mechanistic insights into melatonin-mediated modulation of FGF19/FGFR4 signaling in HNSCC, demonstrating that activating this molecular node confines the role of melatonin in suppressing metastasis and even triggers the switch of its function from anti-metastasis to metastasis promotion. The blockade of FGF19/FGFR4 signaling would have great potential in improving the efficacy of melatonin supplements in cancer treatment.
Databáze: MEDLINE
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