Activation of GDNF-ERK-Runx1 signaling contributes to P2X3R gene transcription and bone cancer pain

Zhu-Lin Yuan; Xiao-Dan Liu; Zi-Xian Zhang; Song Li; Yue Tian; Ke Xi; Jie Cai; Xiao-Mei Yang; Min Liu; Guo-Gang Xing

doi:10.1016/j.isci.2022.104936

Activation of GDNF-ERK-Runx1 signaling contributes to P2X3R gene transcription and bone cancer pain

iScience. 2022 Aug 13;25(9):104936. doi: 10.1016/j.isci.2022.104936. eCollection 2022 Sep 16.

Authors

Zhu-Lin Yuan^{1

2

3}, Xiao-Dan Liu^{1

2

3}, Zi-Xian Zhang^{1

2

3}, Song Li^{1

2

3}, Yue Tian^{1

2

3}, Ke Xi^{1

2

3}, Jie Cai^{1

2

3}, Xiao-Mei Yang⁴, Min Liu^{1

2

3}, Guo-Gang Xing^{1

2

3}

Affiliations

¹ Neuroscience Research Institute, Peking University, Beijing 100191, China.
² Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
³ Key Laboratory for Neuroscience, Ministry of Education of China and National Health Commission of China, Beijing 100191, China.
⁴ Department of Human Anatomy and Embryology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.

Abstract

Bone cancer pain is a common symptom in cancer patients with bone metastases and its underlying mechanisms remain unknown. Here, we report that Runx1 directly upregulates the transcriptional activity of P2X3 receptor (P2X3R) gene promoter in PC12 cells. Knocking down Runx1 in dorsal root ganglion (DRG) neurons suppresses the functional upregulation of P2X3R, attenuates neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats, whereas overexpressing Runx1 promotes P2X3R gene transcription in DRG neurons, induces neuronal hyperexcitability and pain hypersensitivity in naïve rats. Activation of GDNF-GFRα1-Ret-ERK signaling is required for Runx1-mediated P2X3R gene transcription in DRG neurons, and contributes to neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats. These findings indicate that the Runx1-mediated P2X3R gene transcription resulted from activation of GDNF-GFRα1-Ret-ERK signaling contributes to the sensitization of DRG neurons and pathogenesis of bone cancer pain. Our findings identify a potentially targetable mechanism that may cause bone metastasis-associated pain in cancer patients.

Keywords: Molecular biology; Molecular medicine; Molecular physiology; Physiology.