1. Academic Validation
  2. MTNR1B loss promotes chordoma recurrence by abrogating melatonin-mediated β-catenin signaling repression

MTNR1B loss promotes chordoma recurrence by abrogating melatonin-mediated β-catenin signaling repression

  • J Pineal Res. 2019 Sep;67(2):e12588. doi: 10.1111/jpi.12588.
Lei Liu 1 2 3 4 5 Tingting Wang 1 Xiaoming Yang 1 Caixia Xu 6 Zhiheng Liao 1 Xudong Wang 7 Deying Su 1 Yongyong Li 6 Hang Zhou 1 Xianjian Qiu 7 Yuyu Chen 1 Dongsheng Huang 7 Chengjie Lian 1 2 Peiqiang Su 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Orthopaedic Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2 Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3 Guangdong Province Center for Peripheral Nerve Tissue Engineering and Technology Research, Guangzhou, China.
  • 4 Guangdong Province Engineering Laboratory for Soft Tissue Biofabrication, Guangzhou, China.
  • 5 Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 6 Research Centre for Translational Medicine, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 7 Department of Spine Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Abstract

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 Gαi2 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 β-catenin signaling and stemness via decreasing β-catenin p-Y86/Y333/Y654. However, MTNR1B loss in chordoma mediated increased CSC properties, chemoresistance, and tumor progression by releasing melatonin's repression of β-catenin signaling. Clinically, MTNR1B deletion was found to correlate with patients' survival. Together, our study establishes a novel convergence between melatonin and β-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/Gαi2/Src/β-catenin axis.

Keywords

cancer stem cell; chordoma; melatonin; melatonin receptor 1B; β-catenin.

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