A Functional Screen Identifies miRs That Induce Radioresistance in Glioblastomas

Abstract

The efficacy of radiotherapy in many tumor types is limited by normal tissue toxicity and by intrinsic or acquired radioresistance. Therefore, it is essential to understand the molecular network responsible for regulating radiosensitivity/resistance. Here, an unbiased functional screen identified four microRNAs (miR-1, miR-125a, miR-150, and miR-425) that induce radioresistance. Considering the clinical importance of radiotherapy for glioblastoma (GBM) patients, the impact of these miRNAs on GBM radioresistance was investigated. Overexpression of miR-1, miR-125a, miR-150 and/or miR-425 in GBM promotes radioresistance through upregulation of the cell cycle checkpoint response. Conversely, antagonizing with antagomiRs sensitizes GBM cells to irradiation, suggesting their potential as targets for inhibiting therapeutic resistance. Analysis of GBM datasets from TCGA revealed that these miRNAs are expressed in GBM patient specimens and correlate with Transforming Growth Factor Beta (TGF-β) signaling. Finally, it is demonstrated that expression of miR-1 and miR-125a can be induced by TGF-β and antagonized by a TGF-β receptor inhibitor. Together, these results identify and characterize a new role for miR-425, miR-1, miR-125, and miR-150 in promoting radioresistance in GBMs and provide insight into the therapeutic application of TGF-β inhibitors in radiotherapy. Systematic identification of miRs that cause radioresistance in gliomas is important for uncovering predictive markers for radiotherapy or targets for overcoming radioresistance.

Effects of Gas1 on gliomas: a review on current preclinical studies

“…[37,38] Screening of molecular changes after radiotherapy showed overexpression of miR-1, -125a, -144, -150, -151-5p, -221/22, -425 and -1285. [39][40][41][42] The ectopic expression of miR-1, -125a, -150 and -425 increases cell survival and confers radioresistance through the induction of the cellcycle. [39] On the other hand, TGF-α and -β, and the EGFR also contribute to radioresistance in classical-GBM.…”

“…[39][40][41][42] The ectopic expression of miR-1, -125a, -150 and -425 increases cell survival and confers radioresistance through the induction of the cellcycle. [39] On the other hand, TGF-α and -β, and the EGFR also contribute to radioresistance in classical-GBM. [43] Thus, inhibiting TGF-β has been proposed as a treatment since it induces radiosensitivity in gliomas through decreasing the expression of miR-1 and -125a.…”

“…[43] Thus, inhibiting TGF-β has been proposed as a treatment since it induces radiosensitivity in gliomas through decreasing the expression of miR-1 and -125a. [23,39,44] Additionally, miR-221/222 downregulate PTEN, leading to activation of proteins that promote cell proliferation or prevent cell death, such as: AKT, B-cell lymphoma 2 (Bcl-2), Cyclin-D, matrix metallopeptidase 2 and 9, [41,45,46] Interestingly, the phosphorylation of AKT is the main mechanism for developing radioresistance, regardless of the activity of its negative regulator PTEN. [40,41] In summary, molecular analysis could help to reconsider whether conventional treatments are suitable, or therapeutic modifications should be adapted to the requirements of the patient.…”

Biomarkers for glioma immunotherapy: the next generation

“…Patient treatment failure is attributed to GBM cellular heterogeneity and the aggressive diffuse infiltration observed at the tumor margins, which allows resistance to radiotherapy and the cytotoxic agents to propagate under selective pressure [2–5], especially upon tumor recurrence [6], and is further complicated by local and systemic tumor derived immunosuppression. While not yet fully elucidated, the causal mechanisms that link the physiology of the tumor to the dysfunction of the infiltrating and peripheral immune cells are complex and interdependent.…”

“…Motivated in part by the characteristics that make GBM a therapeutic challenge [2, 100–102], glioma research has already seen the clinical impact of high-dimensional, “big data” profiling of the tumor tissue and its immune components on our interpretation of classical biomarkers (Table 1). For example, the cytologically diagnosable 10q23 deletion [103] as a biomarker of tumor etiology and prognosis [104–107] preceded elucidation of the tumor suppressor functions of PTEN and their cross-talk with glioma-specific growth pathways.…”