Abstract
Radiation therapy is a current standard-of-care treatment and is used widely for GBM patients. However, radiation therapy still remains a significant barrier to getting a successful outcome due to the therapeutic resistance and tumor recurrence. Understanding the underlying mechanisms of this resistance and recurrence would provide an efficient approach for improving the therapy for GBM treatment. Here, we identified a regulatory mechanism of CD44 which induces infiltration and mesenchymal shift of GBM. Ionizing radiation (IR)-induced K-RAS/ERK signaling activation elevates CD44 expression through downregulation of miR-202 and miR-185 expression. High expression of CD44 promotes SRC activation to induce cancer stemness and EMT features of GBM cells. In this study, we demonstrate that the K-RAS/ERK/CD44 axis is a key mechanism in regulating mesenchymal shift of GBM cells after irradiation. These findings suggest that blocking the K-RAS activation or CD44 expression could provide an efficient way for GBM treatment.
Highlights
Glioblastoma multiform (GBM) is a grade IV glioma which is the most common and aggressive type of primary brain tumor of the central nervous system and has a poor prognosis
We demonstrated that CD44 acts as a receptor for Hyaluronic acid (HA), and its expression can be induced by ionizing radiation
FACS analysis and sphere formation assay showed that the percentage number of CD44+ /CD24− cells was increased in U87MG cells after radiation treatment (Figure 1E,F)
Summary
Glioblastoma multiform (GBM) is a grade IV glioma which is the most common and aggressive type of primary brain tumor of the central nervous system and has a poor prognosis. The reasons GBM is incurable with multimodal therapy are that tumor cells cannot be removed perfectly with surgery and chemotherapy is not effective because the blood-brain barrier (BBB) exists in the brain. Radiation therapy among these therapies has been reported that plays a crucial role in GBM therapy and has tumor malignancy through the acquisition of radio-resistance [6,7]. Identifying the effective key molecular mechanism in response to radiation in GBM is essential to improve the poor prognosis of GBM patients and the development of therapeutic approach for GBM treatment
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