Abstract
Although radiation therapy is the most effective postoperative adjuvant treatment, it does not substantially improve the long-term outcomes of glioma patients because of the characteristic radioresistance of glioma. We found that R-Spondin1 (Rspo1) expression was elevated in high-grade gliomas and was associated with worse overall survival and disease-free survival. Rspo1 expression was also associated with reduced survival rates in glioma patients after treatment with radiotherapy and temozolomide (RT-TMZ). Importantly, Rspo1 was dramatically upregulated after radiation treatment in patients with glioma. Rspo1 silencing by shRNA potentiated glioma cell death upon radiation treatment. In a xenograft nude mouse model, combining radiation and silencing of Rspo1 potentiated tumor growth inhibition. Thus, combining radiotherapy with silencing of Rspo1 is a potential therapeutic approach.
Highlights
The R-Spondin family is a group of four secreted proteins (Rspo1–4) known to be potent agonists of Wnt signaling with important functions in development, stem cell survival and differentiation, and oncogenesis [1]
Radiation therapy is the primary adjuvant treatment modality known to increase the survival of patients with malignant gliomas, it is not a cure, and 90% of tumors recur inside the irradiated tumor volume [10, 11]
We showed that Rspo1 is frequently upregulated in gliomas (43.4%, 102/235), in high-grade glioma, and that a positive association exists between Rspo1 expression and advanced clinicopathological features
Summary
The R-Spondin (roof plate-specific spondin) family is a group of four secreted proteins (Rspo1–4) known to be potent agonists of Wnt signaling with important functions in development, stem cell survival and differentiation, and oncogenesis [1]. A secreted ~35 kDa molecule, binds to leucine-rich repeat-containing G protein-coupled receptor (LGR) 4–6 and synergizes with soluble Wnt3a to induce LRP6 phosphorylation and promote cytoplasmic stabilization as well as nuclear accumulation of β-catenin for cellular proliferation, differentiation and stem cell maintenance [3]. Radiation therapy is a core therapy for malignant glioma, which consists of concomitant chemoradiotherapy with temozolomide after debulking surgery [9]. Enhancing the effects of radiation, the primary adjuvant treatment for glioma, may increase the survival and quality of life of patients
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