Current and Future Trends on Diagnosis and Prognosis of Glioblastoma: From Molecular Biology to Proteomics

Silantyev, Artemiy; Falzone, Luca; Libra, Massimo; Gurina, O. I.; Kardashova, K. Sh.; Νikolouzakis, Τaxiarchis Κonstantinos; Nosyrev, Alexander E.; Sutton, Chris W.; Mitsias, Panayiotis; Tsatsakis, Aristidis

doi:10.3390/cells8080863

Cited by 190 publications

(150 citation statements)

References 211 publications

(283 reference statements)

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“…Moreover, the significant heterogeneity of this tumor represents a potential source of therapeutic resistance and one of the main hindrances in the identification of new pharmacological targets for the development of more effective drugs. Furthermore, recent studies highlighted a complex crosstalk between tumor cells and the microenvironment, especially enhanced angiogenesis and aberration in anticancer immune response, which could be the cause of more aggressive tumor phenotype and failure of treatments effectiveness [2,5]. All of these issues represent a dramatic challenge for the development of new therapies and raise the need to improve the knowledge of the molecular mechanisms underlying GB tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…The current therapeutic protocol for GB patients consists of surgical resection of tumor mass and subsequent concomitant radiotherapy and chemotherapy. However, these approaches show very limited effectiveness, resulting in a high rate of relapse and subsequent deterioration of the patient's neurological and physiological status [2,5].In the recent years, several genetic and epigenetic aberrations in molecular pathways (i.e., WNT and Hedgehog signaling) [6-9] have been associated with GB onset and progression, representing potential therapeutic targets and biomarkers for early prognosis [2,3,5]. Hence, the identification and characterization of new molecular players involved in GB tumorigenesis is essential for developing more effective and innovative therapies against this aggressive malignancy.Ubiquitylation is a post-translational modification that controls a wide range of cellular functions (i.e., protein degradation, endocytosis and trafficking) and the most important physiological processes [10,11].…”

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confidence: 99%

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confidence: 99%

“…In the recent years, several genetic and epigenetic aberrations in molecular pathways (i.e., WNT and Hedgehog signaling) [6-9] have been associated with GB onset and progression, representing potential therapeutic targets and biomarkers for early prognosis [2,3,5]. Hence, the identification and characterization of new molecular players involved in GB tumorigenesis is essential for developing more effective and innovative therapies against this aggressive malignancy.…”

mentioning

confidence: 99%

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The RNA-Binding Ubiquitin Ligase MEX3A Affects Glioblastoma Tumorigenesis by Inducing Ubiquitylation and Degradation of RIG-I

Bufalieri

Caimano

Severini

et al. 2020

Cancers

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Glioblastoma multiforme (GB) is the most malignant primary brain tumor in humans, with an overall survival of approximatively 15 months. The molecular heterogeneity of GB, as well as its rapid progression, invasiveness and the occurrence of drug-resistant cancer stem cells, limits the efficacy of the current treatments. In order to develop an innovative therapeutic strategy, it is mandatory to identify and characterize new molecular players responsible for the GB malignant phenotype. In this study, the RNA-binding ubiquitin ligase MEX3A was selected from a gene expression analysis performed on publicly available datasets, to assess its biological and still-unknown activity in GB tumorigenesis. We find that MEX3A is strongly up-regulated in GB specimens, and this correlates with very low protein levels of RIG-I, a tumor suppressor involved in differentiation, apoptosis and innate immune response. We demonstrate that MEX3A binds RIG-I and induces its ubiquitylation and proteasome-dependent degradation. Further, the genetic depletion of MEX3A leads to an increase of RIG-I protein levels and results in the suppression of GB cell growth. Our findings unveil a novel molecular mechanism involved in GB tumorigenesis and suggest MEX3A and RIG-I as promising therapeutic targets in GB.Cancers 2020, 12, 321 2 of 16 treatments [2]. The current therapeutic protocol for GB patients consists of surgical resection of tumor mass and subsequent concomitant radiotherapy and chemotherapy. However, these approaches show very limited effectiveness, resulting in a high rate of relapse and subsequent deterioration of the patient's neurological and physiological status [2,5].In the recent years, several genetic and epigenetic aberrations in molecular pathways (i.e., WNT and Hedgehog signaling) [6-9] have been associated with GB onset and progression, representing potential therapeutic targets and biomarkers for early prognosis [2,3,5]. Hence, the identification and characterization of new molecular players involved in GB tumorigenesis is essential for developing more effective and innovative therapies against this aggressive malignancy.Ubiquitylation is a post-translational modification that controls a wide range of cellular functions (i.e., protein degradation, endocytosis and trafficking) and the most important physiological processes [10,11]. Ubiquitylation is mediated by an enzymatic cascade, in which the E3-ubiquitin ligases are the main players, responsible for the recognition of specific substrates and the final transferring of ubiquitin moieties onto target proteins.Deregulation or mutations of E3-ubiquitin ligases have been associated with several human tumors; for this reason, they are considered to be promising targets for novel anticancer therapies [12][13][14]. At present, very little information is available about the role of E3 ligases and ubiquitylation processes in GB development and progression [15][16][17].In this regard, we evaluated the expression levels of catalytic E3-ubiquitin ligase complex components [18] and F-b...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The RNA-Binding Ubiquitin Ligase MEX3A Affects Glioblastoma Tumorigenesis by Inducing Ubiquitylation and Degradation of RIG-I

Bufalieri

Caimano

Severini

et al. 2020

Cancers

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“…Although there are reports suggesting a relationship between the MMR mechanism and miRNA profiles [41,43,44,46], the underlying molecular mechanism by which tobacco smoke carcinogens induce miRNA deregulation and affect the expression profiles of mismatch repair genes, particularly in lung and head and neck cancer, is not yet known.Here, we attempt to explore whether NNK affects the expression of small regulatory molecules, such as known miRNA markers, previously associated with upper aerodigestive tract malignancies [47][48][49][50][51][52][53][54] that may directly or indirectly be involved in the regulation for MMR expression phenotypes. Understanding the molecular changes induced by various risk factors, such as tobacco smoke, which promote the development and progression of cancer, will help to develop new diagnostic and therapeutic approaches [55,56], leading to optimization of their management.…”

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confidence: 99%

The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer Cells

Doukas

Vageli²,

Lazopoulos

et al. 2020

Cells

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Tobacco smoking is a common risk factor for lung cancer and head and neck cancer. Molecular changes such as deregulation of miRNA expression have been linked to tobacco smoking in both types of cancer. Dysfunction of the Mismatch DNA repair (MMR) mechanism has also been associated with a poor prognosis of these cancers, while a cross-talk between specific miRNAs and MMR genes has been previously proposed. We hypothesized that exposure of lung and head and neck squamous cancer cells (NCI and FaDu, respectively) to tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is capable of altering the expression of MSH2 and MLH1, key MMR components, by promoting specific miRNA deregulation. We found that either a low (1 µM) or high (2 µM) dose of NNK induced significant upregulation of "oncomirs" miR-21 and miR-155 and downregulation of "tumor suppressor" miR-422a, as well as the reduction of MMR protein and mRNA expression, in NCI and FaDu, compared to controls. Inhibition of miR-21 restored the NNK-induced reduced MSH2 phenotype in both NCI and FaDu, indicating that miR-21 might contribute to MSH2 regulation. Finally, NNK exposure increased NCI and FaDu survival, promoting cancer cell progression. We provide novel findings that deregulated miR-21, miR-155, and miR-422a and MMR gene expression patterns may be valuable biomarkers for lung and head and neck squamous cell cancer progression in smokers.Cells 2020, 9, 1031 2 of 22 and neck squamous cell carcinoma (HNSCC), represents one of the most aggressive malignancies with a high rate of mortality. [8,9]. Tobacco smoking has been one of the most well-established risk factors for both lung and head and neck cancers [1][2][3][4][5][6][7][8]. It is known that tobacco smoke contains a mixture of thousands of compounds, including a large number of known carcinogens [2]. It is believed that exposure of cells to tobacco smoke carcinogens can lead to DNA damage, which may cause chromosomal instability and increased cell proliferation [10][11][12][13]. In particular, tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is one of the chemicals in tobacco smoke, has been linked to lung and head and neck cancer [14], and has also been shown to upregulate oncogenic pathways [15][16][17].The development and progression of lung and head and neck malignancies appear to be a complex process. Although multiple diagnostic and prognostic markers have been identified for both lung and head and neck cancers [18,19], the precise molecular mechanisms involved in the development and progression of these malignancies remain unclear.We understand that a functional DNA repair mechanism that includes the recognition and repair of mismatch DNA errors during DNA replication is essential in eliminating the harmful effect of several environmental risk factors, such as NNK, on the exposed cells [20][21][22][23]. A number of studies have shown that reduced expression of mismatch DNA repair (MMR) genes increases the incidence of microsatellite ...

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Targeting Glioblastoma: Advances in Drug Delivery and Novel Therapeutic Approaches

Yeini

Ofek

Albeck

et al. 2020

Advanced Therapeutics

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Glioblastoma (GB) is the most lethal type of primary tumor in the central nervous system. Current treatments include surgical resection followed by chemotherapy and radiotherapy. With this therapeutic regimen, the median survival is less than two years. However, these treatments do not much improve the overall survival of GB patients. GBs are highly angiogenic and invasive tumors and often acquire resistance to therapy. The invasive nature of the disease limits the ability to achieve complete resection of the tumor and the majority of GB patients will experience disease relapse. Moreover, GB is highly heterogeneous, harboring different mutations and presenting different phenotypes. As the brain is considered to be an immune‐privileged tissue, GB is defined as a cold tumor for which current immunotherapies have not yet been demonstrated to improve survival. On top of these challenges, the blood brain barrier (BBB) restricts the uptake of drugs by the brain, thus limiting the therapeutic options. Therefore, enormous efforts are being dedicated to the development of novel nanomedicines, which will be able to cross the BBB and specifically target the cancer cells. Here, the current achievements in drug delivery and novel therapeutic approaches for GB therapy are discussed.

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Current and Future Trends on Diagnosis and Prognosis of Glioblastoma: From Molecular Biology to Proteomics

Cited by 190 publications

References 211 publications

The RNA-Binding Ubiquitin Ligase MEX3A Affects Glioblastoma Tumorigenesis by Inducing Ubiquitylation and Degradation of RIG-I

The RNA-Binding Ubiquitin Ligase MEX3A Affects Glioblastoma Tumorigenesis by Inducing Ubiquitylation and Degradation of RIG-I

The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer Cells

Targeting Glioblastoma: Advances in Drug Delivery and Novel Therapeutic Approaches

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