• brain tumors
• drug nanocarriers
• extracellular vesicles (EVs)
• glioblastoma
• liquid biopsy
• tumor biomarkers

• Chemo resistance
• Glioblastoma
• Prognosis
• Temozolomide
• microRNA

• Humans
• Temozolomide/pharmacology
• Temozolomide/therapeutic use
• Glioblastoma/genetics
• Glioblastoma/drug therapy
• Glioblastoma/pathology
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Drug Resistance, Neoplasm/genetics
• Brain Neoplasms/genetics
• Brain Neoplasms/drug therapy
• Brain Neoplasms/pathology
• Animals
• Dacarbazine/analogs & derivatives
• Dacarbazine/therapeutic use
• Dacarbazine/pharmacology
• Autophagy/drug effects
• Autophagy/genetics
• Gene Expression Regulation, Neoplastic/drug effects

• Clinical prediction model
• Deep learning
• Machine learning
• MicroRNA
• Review
• Subcellular distribution
• Target prediction

• MicroRNAs/genetics
• Humans
• Artificial Intelligence
• Neoplasms/genetics
• Algorithms
• Computational Biology/methods
• Machine Learning
• Deep Learning

• predictive markers
• oral cancer detection

• Humans
• MicroRNAs/metabolism
• Carcinoma, Squamous Cell/diagnosis
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/metabolism
• Squamous Cell Carcinoma of Head and Neck/genetics
• Mouth Neoplasms/diagnosis
• Mouth Neoplasms/genetics
• Mouth Neoplasms/metabolism
• Biomarkers, Tumor/metabolism
• Neoplasm Recurrence, Local/diagnosis
• Neoplasm Recurrence, Local/genetics
• Chronic Disease
• Head and Neck Neoplasms/genetics
• Gene Expression Profiling/methods
• Gene Expression Regulation, Neoplastic

• MOP-133640 Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)
• PJT-162380 Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)

• Cancer stem cells
• Glioma
• MT: Non-coding RNAs

• R01 AI050875 NIAID NIH HHS
• R21 AI121700 NIAID NIH HHS

• STAT3
• circRNAs
• glioma
• lncRNAs
• miRNA

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has an exceedingly low median overall survival of only 15 months. Current standard-of-care for GBM consists of gross total surgical resection followed by radiation with concurrent and adjuvant chemotherapy. Temozolomide (TMZ) is the first-choice chemotherapeutic agent in GBM; however, the development of resistance to TMZ often becomes the limiting factor in effective treatment. While O6-methylguanine-DNA methyltransferase repair activity and uniquely resistant populations of glioma stem cells are the most well-known contributors to TMZ resistance, many other molecular mechanisms have come to light in recent years. Key emerging mechanisms include the involvement of other DNA repair systems, aberrant signaling pathways, autophagy, epigenetic modifications, microRNAs, and extracellular vesicle production. This review aims to provide a comprehensive overview of the clinically relevant molecular mechanisms and their extensive interconnections to better inform efforts to combat TMZ resistance.

• Glioblastoma
• chemoresistance
• molecular mechanisms
• temozolomide

The overall survival of brain cancer patients remains grim, with conventional therapies such as chemotherapy and radiotherapy only providing marginal benefits to patient survival. Cancers are complex, with multiple pathways being dysregulated simultaneously. Non-coding RNAs such as microRNA (miRNAs) are gaining importance due to their potential in regulating a variety of targets implicated in the pathology of cancers. This could be leveraged for the development of targeted and personalized therapies for cancers. Since miRNAs can upregulate and/or downregulate proteins, this review aims to understand the role of these miRNAs in primary and metastatic brain cancers. Here, we discuss the regulatory mechanisms of ten miRNAs that are highly dysregulated in glioblastoma and metastatic brain tumors. This will enable researchers to develop miRNA-based targeted cancer therapies and identify potential prognostic biomarkers.

Brain cancer is one among the rare cancers with high mortality rate that affects both children and adults. The most aggressive form of primary brain tumor is glioblastoma. Secondary brain tumors most commonly metastasize from primary cancers of lung, breast, or melanoma. The five-year survival of primary and secondary brain tumors is 34% and 2.4%, respectively. Owing to poor prognosis, tumor heterogeneity, increased tumor relapse, and resistance to therapies, brain cancers have high mortality and poor survival rates compared to other cancers. Early diagnosis, effective targeted treatments, and improved prognosis have the potential to increase the survival rate of patients with primary and secondary brain malignancies. MicroRNAs (miRNAs) are short noncoding RNAs of approximately 18–22 nucleotides that play a significant role in the regulation of multiple genes. With growing interest in the development of miRNA-based therapeutics, it is crucial to understand the differential role of these miRNAs in the given cancer scenario. This review focuses on the differential expression of ten miRNAs (miR-145, miR-31, miR-451, miR-19a, miR-143, miR-125b, miR-328, miR-210, miR-146a, and miR-126) in glioblastoma and brain metastasis. These miRNAs are highly dysregulated in both primary and metastatic brain tumors, which necessitates a better understanding of their role in these cancers. In the context of the tumor microenvironment and the expression of different genes, these miRNAs possess both oncogenic and/or tumor-suppressive roles within the same cancer.

• brain cancer
• cancer metastasis
• glioblastoma
• glioma
• miRNA

MicroRNAs (miRNAs) are endogenous, noncoding, single-stranded RNA molecules of 22 nucleotides in length. MiRNAs have both tumor-suppressive properties and oncogenic properties that can control critical processes in tumors. Mature miR-125b originates from miR-125b-1 and miR-125b-2 and leads to the degradation of target mRNAs or the inhibition of translation through binding to the 3′ untranslated regions (3′-UTR) of target mRNAs. Importantly, miR-125b is involved in regulating NF-κB, p53, PI3K/Akt/mTOR, ErbB2, Wnt, and another signaling pathways, thereby controlling cell proliferation, differentiation, metabolism, apoptosis, drug resistance and tumor immunity. This review aims to summarize the recent literature on the role of miR-125b in the regulation of tumorigenesis and to explore its potential clinical application in the diagnosis, prognosis and clinical treatment of tumors.

• biomarker
• cancer
• miR-125b
• pathway

Purpose: The in vitro environment can influence not only the molecular background of glioblastoma drug-resistance and treatment efficiency, but also the mechanisms and pathways of cell death. Both crucial molecular pathways and the deregulation of miRNAs are thought to participate in tumor therapy-resistance. The aim of our study is to examine the potential influence of ex vivo conditions on the expression of miRNAs engaged in the machinery of tumor-drug resistance, since in vitro models are commonly used for testing new therapeutics.

Methods: Glioblastoma-derived cells, cultured under three different sets of conditions, were used as experimental models in vitro. The expression of 84 miRNAs relevant to brain tumorigenesis was evaluated by multi-miRNA profiling for initial tumors and their corresponding cultures. Finally, the expression of selected miRNAs related to temozolomide-resistance (miR-125b, miR-130a, miR-21, miR-221, miR-222, miR-31, miR-149, miR-210, miR-181a) was assessed by real-time PCR for each tumor and neoplastic cells in cultures.

Results: Our results demonstrate significant discrepancies in the expression of several miRNAs between tumor cells in vivo and in vitro, with miR-130a, miR-221, miR-31, miR-21, miR-222, miR-210 being the most marked. Also differences were observed between particular models in vitro. The results of computational analysis revealed the interplay between examined miRNAs and their targets involved in processes of glioblastoma chemosensitivity, including the genes relevant to temozolomide response (MGMT, PTEN, MDM2, TP53, BBC3A).

Conclusion: The artificial environment may influence the selective proliferation of cell populations carrying specific patterns of miRNAs and/or the phenotype of neoplastic cells (eg differentiation) by the action of molecular events including miRNAs. These phenomena may influence the tumor-responsiveness to particular drugs, disturbing the evaluation of their efficacy in vitro, with unpredictable results caused by the interdependency of molecular pathways.

• cell culture
• drug-resistance
• glioblastoma
• miRNA
• temozolomide

• IKKε inhibitor
• MCCK1
• epithelial-mesenchymal transition
• glioblastoma therapy
• temozolomide

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Apoptosis/drug effects
• Brain Neoplasms/drug therapy
• Brain Neoplasms/pathology
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Drug Synergism
• Epithelial-Mesenchymal Transition/drug effects
• Female
• Glioblastoma/drug therapy
• Glioblastoma/pathology
• Humans
• Mice, Inbred BALB C
• Mice, Nude
• Rosaniline Dyes/pharmacology
• Rosaniline Dyes/therapeutic use
• Temozolomide/pharmacology
• Temozolomide/therapeutic use

• Biological hallmarks
• Biomarker
• Glioblastoma
• MiRNA
• Prognosis
• Therapeutic target

• MYC
• PIAS3
• STAT3
• medulloblastoma
• miR-21

The function of miR16 in multiforme glioblastoma multiforme (GBM) and its stem cells (GSCs) remains elusive. To this end, we investigated the patterns of miR16 expression in these cells and their correlation with malignant behaviors and clinical outcomes. The levels of miR16 and its targeted genes in tumor tissue of GBM and GBM SGH44, U87, U251 cells as well as their stem cell counterparts were measured by qRT–PCR or western blot or immunohistochemistry. Luciferase reporter assay was used to confirm the binding of miR16 to 3′-UTR of its target genes. The effects of miR16 on malignant behaviors were investigated, including tumor cell viability, soft-agar colony formation, GSCs Matrigel colony forming and migration and invasion as well as nude mice xenograft model. Differentially expression patterns of miR16 in glioblastoma cells and GSCs cells were found in this study. Changes of miR16 targeted genes, Bcl2 (B cell lymphoma 2), CDK6 (Cyclin-dependent kinase 6), CCND1 (cyclin D1), CCNE1 (cyclin E1) and SOX5 were confirmed in glioblastoma cell lines and tissue specimens. In vitro and in vivo studies showed that tumor cell proliferation was inhibited by miR16 mimic, but enhanced by miR16 inhibitor. The expression level of miR16 positively correlates with GSCs differentiation, but negatively with the abilities of migration, motility, invasion and colony formation in glioblastoma cells. The inhibitory effects of miR16 on its target genes were also found in nude mice xenograft model. Our findings revealed that the miR16 functions as a tumor suppressor in GSCs and its association with prognosis in GBM.

• Apigenin/pharmacology
• Apoptosis/drug effects
• Brain Neoplasms/drug therapy
• Brain Neoplasms/pathology
• Caspase 3/metabolism
• Cell Line, Tumor
• Cell Survival/drug effects
• Glioma/drug therapy
• Glioma/pathology
• Humans
• Membrane Potential, Mitochondrial/drug effects
• Membrane Potential, Mitochondrial/physiology
• MicroRNAs/antagonists & inhibitors
• MicroRNAs/physiology
• Neoplastic Stem Cells/drug effects
• Proto-Oncogene Proteins c-bcl-2/physiology

Osteosarcoma (OS) is the most common primary bone malignancy and remains a leading cause of cancer-related deaths in adolescents. Emerging evidence indicates that microRNAs (miRNAs) are correlated with clinical and biological characteristics of OS. However, the involvement of miR-199a-5p in OS development remains unclear. In this study, we examined the function of miR-199a-5p in vitro and in vivo. The results showed that miR-199a-5p was significantly up-regulated in OS patient tissues and cells. The inhibition of miR-199a-5p led to a significant decrease in cell proliferation and tumour growth. We further demonstrated that miR-199a-5p could directly bind to the 3′UTRs of the mRNA of both PIAS3 and p27 and mediate a decrease in the protein levels of PIAS3 and p27, thereby stimulating STAT3 activation and cell cycle progression in OS cells. Rescue experiments of PIAS3 and p27 further revealed that PIAS3 and p27 were functional targets of miR-199a-5p. Moreover, enhancing the expressions of both PIAS3 and p27 using miR-199a-5p-targeted inhibitors in an OS xenograft model was shown to be a promising approach for OS clinical therapy. Our findings indicate that the pathway of miR-199a-5p targeting both PIAS3 and p27 is a possible mechanism that contributes to tumour growth in OS.

Emerging evidence has demonstrated that microRNAs (miRNA) play a critical role in chemotherapy-induced epithelial-mesenchymal transition (EMT) in breast cancer. However, the underlying mechanism of chemotherapy-mediated EMT has not been fully understood. To address this concern, we explored the role of miR-125b in regulation of EMT in stable paclitaxel-resistant (PR) breast cancer cells, namely MCF-7 PR and SKBR3 PR, which have displayed mesenchymal features. Our results illustrated that miR-125b was significantly downregulated in PR cells. Moreover, ectopic expression of miR-125b by its mimics reversed the phenotype of EMT in PR cells. Furthermore, we found that miR-125b governed PR-mediate EMT partly due to governing its target Sema4C. More importantly, overexpression of miR-125b or depletion of Sema4C sensitized PR cells to paclitaxel. These findings suggest that up-regulation of miR-125b or targeting Sema4C could serve as novel approaches to reverse chemotherapy resistance in breast cancers.

• Carcinoma
• Epidermis
• Hair
• MicroRNAs
• Regenerative medicine
• Squamous cell
• Stem cells

• Cancer stem cells
• Cancer therapy
• Drug resistance
• MicroRNAs
• Tumor recurrence

• Glioblastoma (GBM)
• blood-brain barrier (BBB)
• clinical trial
• targeted therapy

• microrna
• signal regulator
• regulon
• jak-stat
• nf-κb
• tgf-β
• transcriptome-wide

• Animals
• Gene Expression Regulation/genetics
• Humans
• MicroRNAs/genetics
• Signal Transduction/genetics
• Transcription Factors/genetics

• Science Foundation Ireland

O-6-methylguanine-DNA methyltransferase (MGMT) is an abundantly expressed nuclear protein dealkylating O⁶-methylguanine (O⁶-MG) DNA residue, thus correcting the mismatches of O⁶-MG with a thymine residue during DNA replication. The dealkylating effect of MGMT is relevant not only in repairing DNA mismatches produced by environmental alkylating agents promoting tumor pathogenesis, but also when alkylating molecules are applied in the chemotherapy of different cancers, including glioma, the most common primary tumor of the central nervous system. Elevated MGMT gene expression is known to confer resistance to the treatment with the alkylating drug temozolomide in patients affected by gliomas and, on the contrary, methylation of MGMT gene promoter, which causes reduction of MGMT protein expression, is known to predict a favourable response to temozolomide. Thus, detecting expression levels of MGMT gene is crucial to indicate the option of alkylating agents or to select patients directly for a second line targeted therapy. Further study is required to gain insights into MGMT expression regulation, that has attracted growing interest recently in MGMT promoter methylation, histone acetylation and microRNAs expression. The review will focus on the epigenetic regulation of MGMT gene, with translational applications to the identification of biomarkers predicting response to therapy and prognosis.

• Apoptosis
• Demethoxycurcumin
• Glioblastoma stem cell
• Proliferation
• Temozolomide

• Apoptosis/drug effects
• Caspase 3/genetics
• Cell Proliferation/drug effects
• Curcumin/administration & dosage
• Curcumin/analogs & derivatives
• Dacarbazine/administration & dosage
• Dacarbazine/analogs & derivatives
• Diarylheptanoids
• Glioblastoma/drug therapy
• Glioblastoma/genetics
• Glioblastoma/pathology
• Humans
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/pathology
• Primary Cell Culture
• Reactive Oxygen Species/metabolism
• Signal Transduction/drug effects
• Temozolomide

• Glioblastoma
• Hedgehog
• Invasion
• PI3K
• Wnt

• Glioblastoma
• Stemness
• Tumor suppressor
• miR-218
• miRNA