RUNX1 (RUNX family transcription factor 1), a target of microRNA miR-128-3p, promotes temozolomide resistance in glioblastoma multiform by upregulating multidrug resistance-associated protein 1 (MRP1)

Abstract

Glioblastoma multiform (GBM) is the most frequent type of malignant brain tumor with a poor prognosis. After optimal surgery, radiotherapy plus temozolomide (TMZ) is the standard treatment for GBM patients. However, the development of TMZ resistance limits its efficacy in GBM management. Runt Related Transcription Factor 1 (RUNX1) and microRNAs have been implicated in drug resistance of TMZ in GBM. In this study, we revealed the underlying mechanism of TMZ resistance and identified miR-128-3p/RUNX1 axis as a novel target for TMZ resistance in GBM. RUNX1 expression was significantly upregulated in GBM tissues as compared to normal tissues, and its expression was even higher in recurrent GBM tissues and TMZ-resistant GBM cells. RUNX1 depletion inhibited the viability, proliferation, migration, invasion and TMZ resistance of GBM cells, which could be rescued by RUNX1 overexpression. We further identified miR-128-3p as a tumor-suppressor whose overexpression restored the sensitivity of TMZ in GBM cells. miR-128-3p negatively regulated RUNX1 and subsequently downregulated multidrug resistance-associated protein 1 (MRP1). Together, the present study indicates that RUNX1 confers TMZ resistance in GBM by upregulating MRP1, which is negatively regulated by miR-128-3p. Targeting miR-128-3p/RUNX1/MRP1 axis provides a potential strategy to overcome TMZ resistance in GBM.

RUNX1 is regulated by androgen receptor to promote cancer stem markers and chemotherapy resistance in triple negative breast cancer

“…This observation is supported by accumulated evidence suggesting that CSC are the remaining population that survives drug treatments and regenerates tumors [48]. RUNX1 participation in chemotherapy drug response has also been reported in ovarian cancer [59], glioblastoma multiforme [60] and colorectal cancer [61], suggesting that this function could be a general molecular mechanism of action that favors tumor aggressiveness against cytostatic drug treatment. In vivo experiments have yet to be performed to continue exploring this concept in triple negative breast cancer.…”

The role of miR-128 in cancer development, prevention, drug resistance, and immunotherapy

“…Glioblastoma is the most severe type of glioma and the most common invasive and lethal brain tumor in children and adults with a catastrophic prognosis ( 82 , 146 ). The expression of Runt-related transcription factor 1 (RUNX1) is significantly higher in the mesenchymal subtype of glioblastoma and is strongly linked to the mesenchymal subtype initiated through miRNA-mediated pathways ( 147 ).…”

“…A growing body of data indicates that multidrug resistance protein 1 (MRP1), which is upregulated in cancers, modulates cellular chemoresistance, and temozolomide has been identified as a target of MRP1 ( 151 , 152 ). In conclusion, Zhou and colleagues investigated the underlying mechanisms of temozolomide tolerance and discovered the miR-128-3p/RUNX1 pathway as a novel target for temozolomide tolerance in glioblastoma ( 82 ). They confirmed the oncogenic involvement of RUNX1 in glioblastoma cells and discovered miR-128-3p as a potent inhibitor of RUNX1.…”

“…They confirmed the oncogenic involvement of RUNX1 in glioblastoma cells and discovered miR-128-3p as a potent inhibitor of RUNX1. The researchers also discovered that RUNX1 upregulated MRP1 to induce temozolomide tolerance ( 82 ). These findings suggest that miR-128-3p/RUNX1/MRP1 axis modulates temozolomide resistance in glioblastoma cells, and these molecules may be used to regulate temozolomide responsiveness in glioblastoma.…”

Systematic characterization and biological functions of non‐coding RNAs in glioblastoma

“…The average survival time of patients with glioma is 12–15 months, the 5‐year survival rate is <5%, and the survival and prognosis of patients with GBM are worse 22 ; thus, it is important to evaluate the patient's prognosis. High expression of miR‐1258 , miR‐935 and miR‐128‐3p was associated with better overall survival (OS) in patients with GBM, 23 , 24 , 25 while low miR‐542‐3p and miR‐221/222 clusters expression was associated with better OS in patients with GBM. 26 , 27 Previous studies evaluated the effect of cell‐free circulating RNA on patients with GBM.…”