Abstract
Ewing sarcoma (EwS) is a rare and highly malignant bone tumor occurring mainly in childhood and adolescence. Physiologically, the bone is a central hub for Ca2+ homeostasis, which is severely disturbed by osteolytic processes in EwS. Therefore, we aimed to investigate how ion transport proteins involved in Ca2+ homeostasis affect EwS pathophysiology. We characterized the expression of 22 candidate genes of Ca2+-permeable or Ca2+-regulated ion channels in three EwS cell lines and found the Ca2+-activated K+ channel KCa2.1 (KCNN1) to be exceptionally highly expressed. We revealed that KCNN1 expression is directly regulated by the disease-driving oncoprotein EWSR1-FL1. Due to its consistent overexpression in EwS, KCNN1 mRNA could be a prognostic marker in EwS. In a large cohort of EwS patients, however, KCNN1 mRNA quantity does not correlate with clinical parameters. Several functional studies including patch clamp electrophysiology revealed no evidence for KCa2.1 function in EwS cells. Thus, elevated KCNN1 expression is not translated to KCa2.1 channel activity in EwS cells. However, we found that the low K+ conductance of EwS cells renders them susceptible to hypoosmotic solutions. The absence of a relevant K+ conductance in EwS thereby provides an opportunity for hypoosmotic therapy that can be exploited during tumor surgery.
Funder
Maria-Möller Stiftung
Deutsche Forschungsgemeinschaft
Reference69 articles.
1. Osteosarcoma, Chondrosarcoma and Ewing Sarcoma: Clinical Aspects, Biomarker Discovery and Liquid Biopsy;Aran;Crit. Rev. Oncol./Hematol.,2021
2. Zöllner, S.K., Amatruda, J.F., Bauer, S., Collaud, S., de Álava, E., Dubois, S.G., Hardes, J., Hartmann, W., Kovar, H., Metzler, M., Ewing Sarcoma—Diagnosis, Treatment, Clinical Challenges and Future Perspectives. J. Clin. Med., 2021. 10.
3. Chimeric EWSR1-FLI1 Regulates the Ewing Sarcoma Susceptibility Gene EGR2 via a GGAA Microsatellite;Grünewald;Nat. Genet.,2015
4. Ewing Sarcoma: Current Management and Future Approaches Through Collaboration;Gaspar;J. Clin. Oncol.,2015
5. Normal Bone Anatomy and Physiology;Clarke;Clin. J. Am. Soc. Nephrol.,2008
Cited by
4 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献