In mesenchymal stem cells, SFRP2 overexpression inhibits Wnt signaling by decreasing β-catenin level. Secreted frizzled-related protein 2 (SFRP2), a key member of the SFRP family, can act as antagonist or agonist for Wnt signaling, which seems to be context dependent. These members are glycoproteins with a frizzled-like cysteine-rich domain, thus can bind with Wnt ligands or frizzled receptors to regulate Wnt signaling.
The secreted frizzled-related protein (SFRP) family has five members: SFRP1, SFRP2, SFRP3, SFRP4 and SFRP5. For example, cyclophilin A facilitates stemness, self-renewal and radioresistance of GSCs by activating Wnt/β-catenin signaling. In addition, activation of Wnt/β-catenin signaling is reported to promote radioresistance of glioma cells, too. Wnt/β-catenin signaling is also vital for the maintenance of GSCs. Aberrant activation of Wnt/β-catenin signaling is involved in the tumorigenesis and chemo-radioresistance of glioma. Wnt/β-catenin signaling plays an important role in regulating self-renewal and differentiation during the development of central nervous system. There is evidence that CD133+ glioma cells have survival advantages than CD133- glioma cells after radiation. For example, overexpression of PAF promotes GSCs maintenance and self-renewal, thus enhances radioresistance of glioma cells. In addition, GSCs are demonstrated resisting to radiotherapy. The existence of glioma stem cells (GSCs) are proved by a variety of studies. Cancer stem cells are a subset of tumor cells that possess the ability to self-renew and differentiate into other types of tumor cells. Thus, a thoroughly understanding of the molecular mechanism of glioma radioresistance might help to develop novel strategies to improve radiosensitivity.Īccumulated studies indicate that existing of glioma stem cells and activation of Wnt/β-catenin signaling might contribute to radioresistance of glioma cells. However, the effect of radiotherapy is limited due to intrinsic or acquired resistance of glioma cells. Radiotherapy is the first treatment that proves to be effective in high-grade gliomas by randomized trials. The treatment options for high-grade gliomas include maximal surgical resection, radiotherapy and chemotherapy.
Glioblastoma has the poorest prognosis among all gliomas, with a median survival of 15 months and 5-year survival rate less than 5%. For instance, the survival for low-grade gliomas (grade I-II) is 5 to 15 years, and 2 to 3 years for grade III gliomas. Survival of glioma patients varies greatly by histologic type and grade. The age-adjusted incidence for all gliomas is 4.67 to 5.73 per 100 000 persons. Glioblastoma multiforme (GBM, grade IV astrocytoma) is the most common (>50%) and malignant form of glioma. 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). It is the most common and aggressive form of brain cancer, accounting for more than 80% malignant tumors in the central nervous system. Glioma arises from glia, the supporting tissue of brain. 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. 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. SFRP2 knockdown activated Wnt/β-catenin signaling in glioma cell lines, while overexpression of SFRP2 inhibited Wnt/β-catenin activation. Moreover, Wnt/β-catenin signaling was activated in radiotherapy treated glioma patients. CRISP/Cas9-meidated SFRP2 knockdown promoted soft agar colony formation, cancer stemness and radioresistance of glioma cells, while enforced SFRP2 expression exhibited opposite effects. We found that SFRP2 was downregulated in radiotherapy-treated glioma patients, and low SFRP2 expression was correlated with advanced tumor stage and poor prognosis.
The potential functions of SFRP2 in glioma were evaluated by loss-of-function assays and gain-of-function assays in glioma cell lines. SFRP2 expression in 166 glioma patients was evaluated by qRT-PCR.
The RNA sequencing data of TCGA glioma samples were downloaded and analyzed. In the present study, we aimed to explore the potential function of SFRP2 in tumorigenesis and radioresistance of glioma. 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. 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.
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