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INTERNATIONAL CONGRESS OF

CancerGenetics

• Therapeutic potential of miRNA modulation to overcome Temozolomide resistance in Glioblastoma

• Masoumeh Ghavami Moshfegh ,^1,* Fatemeh Bahreini,²
  1. Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
  2. 1. Department of Medical Genetics, Hamadan University of Medical Sciences, Hamadan, Iran 2. Research Center for Molecular Medicine, Institute of Cancer, Hamadan University of Medical Sciences, Hamadan, Iran
  
  
  
• Introduction: Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor in adults, marked by rapid proliferation, diffuse infiltration, and poor therapeutic response. Despite multimodal treatment including surgical resection, radiotherapy, and chemotherapy—the median survival of GBM patients remains between 12 and 15 months .Temozolomide (TMZ), an oral alkylating agent, is the standard chemotherapeutic used alongside radiotherapy. However, both intrinsic and acquired resistance to TMZ significantly limit its clinical efficacy. Recent research has highlighted the role of microRNAs (miRNAs) small non-coding RNAs that regulate gene expression post transcriptionally in modulating TMZ resistance. These molecules influence key cellular processes such as DNA repair, apoptosis, autophagy, and drug efflux. Importantly, several studies have validated the function of miRNAs in in vivo models, underscoring their translational relevance.For instance, miR-155-3p was shown to promote TMZ resistance and tumor growth in mouse models by activating the Six1 axis. Similarly, miR-519a-3p enhanced resistance through the HOTAIR/RRM1 pathway in vivo, while miR-204-5p suppressed TXNIP and activated the Nrf2/ARE pathway in animal models, contributing to chemoresistance. Resistance transfer via extracellular vesicles was also demonstrated in vivo for miR-27a-3p and miR-1238, confirming their role in intercellular communication of drug resistance. Conversely, tumor-suppressive miRNAs have shown promise in sensitizing GBM to TMZ in vivo. miR-486-3p, upregulated by Allicin, downregulated MGMT and improved TMZ response in mouse models. miR-138 promoted caspase-dependent apoptosis and prolonged survival in orthotopic xenografts .while miR-34a, delivered via nanocell platforms, simultaneously inhibited RTK, p53, and Rb pathways, reversing resistance in patient-derived xenografts. Other miRNAs such as miR-218-5p, miR-1297, miR-9-5p, and miR-146a have also demonstrated therapeutic efficacy in vivo by targeting lncRNAs, efflux transporters, and stemness pathways. These in vivo findings not only validate the mechanistic roles of miRNAs but also highlight their potential as therapeutic targets and prognostic biomarkers. This systematic review aims to synthesize current evidence on miRNA-mediated regulation of TMZ resistance in GBM, with a particular focus on studies that demonstrate functional relevance in animal models. By categorizing miRNAs based on their oncogenic or tumor-suppressive roles, and analyzing their molecular mechanisms, this review provides a comprehensive framework for future translational research in GBM therapy.
• Methods: A systematic review was conducted to evaluate the role of microRNAs (miRNAs) in modulating temozolomide (TMZ) resistance in glioblastoma (GBM). Searches were performed in PubMed, Scopus, Web of Science, and Google Scholar (2012–2025) using terms related to GBM, TMZ, miRNAs, and in vivo models. Only original studies with animal experiments or xenografts providing mechanistic insights were included, while purely in vitro studies were excluded. Data extracted included investigated miRNAs, type of in vivo model, target genes and pathways, TMZ treatment protocol,delivery methods, and therapeutic outcomes.
• Results: Several oncogenic miRNAs were identified as promoters of resistance. miR-155-3p activated the Six1 axis, miR-519a-3p enhanced resistance through HOTAIR/RRM1, and miR-204-5p acted via the Nrf2/ARE pathway. Vesicle-mediated transfer of miR-27a-3p and miR-1238 also conferred resistance, highlighting intercellular communication. Conversely, tumor-suppressive miRNAs sensitized tumors to TMZ. miR-486-3p, upregulated by Allicin, suppressed MGMT; miR-138 promoted apoptosis; and miR-34a, delivered through nanocells, inhibited RTK, p53, and Rb pathways. Other miRNAs, including miR-218-5p and miR-146a, further enhanced TMZ response. Collectively, these miRNAs were shown to regulate DNA repair, apoptosis, autophagy, and drug efflux in vivo, underscoring their dual oncogenic and tumor-suppressive roles.
• Conclusion: In vivo evidence confirms that miRNAs are central modulators of TMZ resistance in GBM, functioning as both drivers of chemoresistance and sensitizers to therapy. While they represent promising therapeutic and prognostic tools, major challenges remain, including GBM heterogeneity, variability in animal models, and delivery across the blood–brain barrier. Future research should emphasize standardized models, safe and efficient delivery platforms, and early-phase clinical trials. Translation of these findings into clinical practice may ultimately enhance TMZ efficacy and improve patient outcomes.
• Keywords: Glioblastoma, miRNA, Temozolamide, resistance, sensitivity