Activation of GDNF-ERK-Runx1 Signaling Contributes to P2X3R Gene Transcription and Bone Cancer Pain

Overview

Journal iScience

Publisher Cell Press

Date 2022 Sep 8

PMID 36072549

Authors

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

Affiliations

Soon will be listed here.

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.

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References

Xiang Z, Xiong Y, Yan N, Li X, Mao Y, Ni X . Functional up-regulation of P2X 3 receptors in the chronically compressed dorsal root ganglion. Pain. 2008; 140(1):23-34. PMC: 2667225. DOI: 10.1016/j.pain.2008.07.006. View

Ito Y . Molecular basis of tissue-specific gene expression mediated by the runt domain transcription factor PEBP2/CBF. Genes Cells. 2000; 4(12):685-96. DOI: 10.1046/j.1365-2443.1999.00298.x. View

Gattenloehner S, Chuvpilo S, Langebrake C, Reinhardt D, Muller-Hermelink H, Serfling E . Novel RUNX1 isoforms determine the fate of acute myeloid leukemia cells by controlling CD56 expression. Blood. 2007; 110(6):2027-33. DOI: 10.1182/blood-2007-02-074203. View

Kurtzeborn K, Kwon H, Kuure S . MAPK/ERK Signaling in Regulation of Renal Differentiation. Int J Mol Sci. 2019; 20(7). PMC: 6479953. DOI: 10.3390/ijms20071779. View

He D, Gao Y, Wang S, Xie Z, Song X . Systematic Administration of B Vitamins Alleviates Diabetic Pain and Inhibits Associated Expression of P2X3 and TRPV1 in Dorsal Root Ganglion Neurons and Proinflammatory Cytokines in Spinal Cord in Rats. Pain Res Manag. 2020; 2020:3740162. PMC: 7035549. DOI: 10.1155/2020/3740162. View

Kim D, Khoury-Hanold W, Jain P, Klein J, Kong Y, Pope S . RUNX Binding Sites Are Enriched in Herpesvirus Genomes, and RUNX1 Overexpression Leads to Herpes Simplex Virus 1 Suppression. J Virol. 2020; 94(22). PMC: 7592204. DOI: 10.1128/JVI.00943-20. View

Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A . Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002; 3(7):RESEARCH0034. PMC: 126239. DOI: 10.1186/gb-2002-3-7-research0034. View

Hammarberg H, Piehl F, Cullheim S, Fjell J, Hokfelt T, Fried K . GDNF mRNA in Schwann cells and DRG satellite cells after chronic sciatic nerve injury. Neuroreport. 1996; 7(4):857-60. DOI: 10.1097/00001756-199603220-00004. View

Bangaru M, Park F, Hudmon A, McCallum J, Hogan Q . Quantification of gene expression after painful nerve injury: validation of optimal reference genes. J Mol Neurosci. 2011; 46(3):497-504. PMC: 3273664. DOI: 10.1007/s12031-011-9628-x. View

10.

Zheng Q, Fang D, Liu M, Cai J, Wan Y, Han J . Suppression of KCNQ/M (Kv7) potassium channels in dorsal root ganglion neurons contributes to the development of bone cancer pain in a rat model. Pain. 2013; 154(3):434-448. DOI: 10.1016/j.pain.2012.12.005. View

11.

Chen Y, Zhang X, Wang C, Li G, Gu Y, Huang L . Activation of P2X7 receptors in glial satellite cells reduces pain through downregulation of P2X3 receptors in nociceptive neurons. Proc Natl Acad Sci U S A. 2008; 105(43):16773-8. PMC: 2575495. DOI: 10.1073/pnas.0801793105. View

12.

Qu X, Cai J, Li M, Chi Y, Liao F, Liu F . Role of the spinal cord NR2B-containing NMDA receptors in the development of neuropathic pain. Exp Neurol. 2008; 215(2):298-307. DOI: 10.1016/j.expneurol.2008.10.018. View

13.

Epner D, Partin A, Schalken J, Isaacs J, Coffey D . Association of glyceraldehyde-3-phosphate dehydrogenase expression with cell motility and metastatic potential of rat prostatic adenocarcinoma. Cancer Res. 1993; 53(9):1995-7. View

14.

Burgard E, Niforatos W, van Biesen T, Lynch K, Touma E, Metzger R . P2X receptor-mediated ionic currents in dorsal root ganglion neurons. J Neurophysiol. 1999; 82(3):1590-8. DOI: 10.1152/jn.1999.82.3.1590. View

15.

Chen C, Broom D, Liu Y, de Nooij J, Li Z, Cen C . Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain. Neuron. 2006; 49(3):365-77. DOI: 10.1016/j.neuron.2005.10.036. View

16.

Yoshikawa M, Senzaki K, Yokomizo T, Takahashi S, Ozaki S, Shiga T . Runx1 selectively regulates cell fate specification and axonal projections of dorsal root ganglion neurons. Dev Biol. 2007; 303(2):663-74. DOI: 10.1016/j.ydbio.2006.12.007. View

17.

Vilceanu D, Honore P, Hogan Q, Stucky C . Spinal nerve ligation in mouse upregulates TRPV1 heat function in injured IB4-positive nociceptors. J Pain. 2009; 11(6):588-99. PMC: 2879455. DOI: 10.1016/j.jpain.2009.09.018. View

18.

Surprenant A, North R . Signaling at purinergic P2X receptors. Annu Rev Physiol. 2008; 71:333-59. DOI: 10.1146/annurev.physiol.70.113006.100630. View

19.

He J, Wang X, Liang C, Yao X, Zhang Z, Yang R . Wnt5b/Ryk-mediated membrane trafficking of P2X3 receptors contributes to bone cancer pain. Exp Neurol. 2020; 334:113482. DOI: 10.1016/j.expneurol.2020.113482. View

20.

Nencini S, Ringuet M, Kim D, Greenhill C, Ivanusic J . GDNF, Neurturin, and Artemin Activate and Sensitize Bone Afferent Neurons and Contribute to Inflammatory Bone Pain. J Neurosci. 2018; 38(21):4899-4911. PMC: 6596122. DOI: 10.1523/JNEUROSCI.0421-18.2018. View