Abstract
Secreted frizzled-related protein 2 (SFRP2) is a glycoprotein with frizzled-like cysteine-rich domain that binds with Wnt ligands or frizzled receptors to regulate Wnt signaling. SFRP2 is frequently hypermethylated in glioma patients, and analysis of TCGA data indicates that SFRP2 is one of the most downregulated genes in radiotherapy treated glioma patients. In the present study, we aimed to explore the potential function of SFRP2 in tumorigenesis and radioresistance of glioma. The RNA sequencing data of TCGA glioma samples were downloaded and analyzed. SFRP2 expression in 166 glioma patients was evaluated by qRT-PCR. The potential functions of SFRP2 in glioma were evaluated by loss-of-function assays and gain-of-function assays in glioma cell lines. We found that SFRP2 was downregulated in radiotherapy-treated glioma patients, and low SFRP2 expression was correlated with advanced tumor stage and poor prognosis. CRISP/Cas9-meidated SFRP2 knockdown promoted soft agar colony formation, cancer stemness and radioresistance of glioma cells, while enforced SFRP2 expression exhibited opposite effects. Moreover, Wnt/β-catenin signaling was activated in radiotherapy treated glioma patients. SFRP2 knockdown activated Wnt/β-catenin signaling in glioma cell lines, while overexpression of SFRP2 inhibited Wnt/β-catenin activation. Besides, pharmacological inhibition of Wnt/β-catenin signaling by XAV-939 abrogated the effects of SFRP2 knockdown on cancer stemness and radioresistance of glioma cells. Our data for the first time demonstrated a role of SFRP2 in radioresistance of glioma cells, and suggested that inhibition of Wnt/β-catenin signaling might be a potential strategy for increasing radiosensitivity of glioma patients.
Highlights
Glioma arises from glia, the supporting tissue of brain
We found that Secreted frizzled-related protein 2 (SFRP2) was downregulated in radiotherapy treated glioma patients, and low SFPR2 expression was correlated with advanced tumor stage and poor prognosis
We focused on SFRP2 because it ranked the first in the downregulated genes (Fig 1A, S1 Table), and previous studies indicate that SFRP2 acts as a tumor-suppressor in glioma and regulates Wnt signaling activation in various cancers [17,20,21]
Summary
Glioma arises from glia, the supporting tissue of brain. It is the most common and aggressive form of brain cancer, accounting for more than 80% malignant tumors in the central nervous system [1]. According to the World Health Organization (WHO) classification, glioma can be classified into different histologic types such as astrocytoma (grade I-IV), oligodendroglioma (grade II-III) and oligoastrocytoma (grade II-III) [2]. Glioblastoma multiforme (GBM, grade IV astrocytoma) is the most common (>50%) and malignant form of glioma [2]. The ageadjusted incidence for all gliomas is 4.67 to 5.73 per 100 000 persons [3].
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