Journal
JOURNAL OF PINEAL RESEARCH
Volume 67, Issue 2, Pages -Publisher
WILEY
DOI: 10.1111/jpi.12588
Keywords
cancer stem cell; chordoma; melatonin; melatonin receptor 1B; beta-catenin
Categories
Funding
- three major construction scientific research and cultivation special projects of sun yat-sen university [80000-18833402]
- Fundamental Research Funds for the Central Universities [17ykpy06]
- Natural Science Foundation of Guangdong Province [2018A0303130260]
- National Natural Science Foundation of China [81572091, 81772293, 81772302]
- China Postdoctoral Science Foundation [2017M622873]
- Guangzhou Science and Technology Project [201704020120, 201803010122, 201804010057]
- First Affiliated Hospital of Sun Yat-sen University Three in Three Project
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Chordoma is an extremely rare malignant bone tumor with a high rate of relapse. While cancer stem cells (CSCs) are closely associated with tumor recurrence, which depend on its capacity to self-renew and induce chemo-/radioresistance, whether and how CSCs participate in chordoma recurrence remains unclear. The current study found that tumor cells in recurrent chordoma displayed more dedifferentiated CSC-like properties than those in corresponding primary tumor tissues. Meanwhile, MTNR1B deletion along with melatonin receptor 1B (MTNR1B) down-regulation was observed in recurrent chordoma. Further investigation revealed that activation of G alpha i2 by MTNR1B upon melatonin stimulation could inhibit SRC kinase activity via recruiting CSK and SRC, increasing SRC Y530 phosphorylation, and decreasing SRC Y419 phosphorylation. This subsequently suppressed beta-catenin signaling and stemness via decreasing beta-catenin p-Y86/Y333/Y654. However, MTNR1B loss in chordoma mediated increased CSC properties, chemoresistance, and tumor progression by releasing melatonin's repression of beta-catenin signaling. Clinically, MTNR1B deletion was found to correlate with patients' survival. Together, our study establishes a novel convergence between melatonin and beta-catenin signaling pathways and reveals the significance of this cross talk in chordoma recurrence. Besides, we propose that MTNR1B is a potential biomarker for prediction of chordoma prognosis and selection of treatment options, and chordoma patients might benefit from targeting MTNR1B/G alpha i2/SRC/beta-catenin axis.
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