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  • 1
    Online Resource
    Online Resource
    WNT/β-Catenin-Mediated Resistance to Glucose Deprivation in Glioblastoma Stem-like Cells
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 13 ( 2022-06-28), p. 3165-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 13 ( 2022-06-28), p. 3165-
    Abstract: Isocitrate dehydrogenase (IDH)-wildtype glioblastoma is the most common primary malignant brain tumor. It is associated with a particularly poor prognosis, as reflected by an overall median survival of only 15 months in patients who undergo a supramarginal surgical reduction of the tumor mass followed by combined chemoradiotherapy. The highly malignant nature of IDH-wildtype glioblastoma is thought to be driven by glioblastoma stem-like cells (GSCs) that harbor the ability of self-renewal, survival, and adaptability to challenging environmental conditions. The wingless (WNT) signaling pathway is a phylogenetically highly conserved stemness pathway, which promotes metabolic plasticity and adaptation to a nutrient-limited tumor microenvironment. To unravel the reciprocal regulation of the WNT pathway and the nutrient-limited microenvironment, glioblastoma cancer stem-like cells were cultured in a medium with either standard or reduced glucose concentrations for various time points (24, 48, and 72 h). Glucose depletion reduced cell viability and facilitated the survival of a small population of starvation-resistant tumor cells. The surviving cells demonstrated increased clonogenic and invasive properties as well as enhanced chemosensitivity to pharmacological inhibitors of the WNT pathway (LGK974, berberine). Glucose depletion partially led to the upregulation of WNT target genes such as CTNNB1, ZEB1, and AXIN2 at the mRNA and corresponding protein levels. LGK974 treatment alone or in combination with glucose depletion also altered the metabolite concentration in intracellular compartments, suggesting WNT-mediated metabolic regulation. Taken together, our findings suggest that WNT-mediated metabolic plasticity modulates the survival of GSCs under nutrient-restricted environmental conditions.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14133165
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 2
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    Online Resource
    Regulator of G Protein Signaling 20 Correlates with Long Intergenic Non-Coding RNA (lincRNAs) Harboring Oncogenic Potential and Is Markedly Upregulated in Hepatocellular Carcinoma
    MDPI AG ; 2022
    In:  Biology Vol. 11, No. 8 ( 2022-08-04), p. 1174-
    Details
    In: Biology, MDPI AG, Vol. 11, No. 8 ( 2022-08-04), p. 1174-
    Abstract: Hepatocellular carcinoma (HCC) is at the forefront of the global cancer burden, and biomarkers for HCC are constantly being sought. Interestingly, RGS (Regulators of G protein signaling) proteins, which negatively regulate GPCR signaling, have been associated with various cancers, with some members of the RGS family being associated with liver cancer as well. Considering this, we investigated the role of RGS20 as a potential prognostic marker in 28 different cancer types with special emphasis on HCC. By using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data, our analysis revealed that (a) RGS20 was strongly upregulated in tumor tissue compared with adjacent normal tissue of HCC patients; (b) RGS20 was strongly associated with some important clinical parameters such as alpha-fetoprotein and tumor grade in the HCC patients; (c) besides HCC (p 〈 0.001), RGS20 was found to be an important factor for survival in four other cancers (clear renal cell carcinoma: p 〈 0.001, lung adenocarcinoma: p = 0.004, mesothelioma: p = 0.039, ovarian serous cystadenocarcinoma: p = 0.048); (d) RGS20 was found to be significantly associated with some tumor-related signaling pathways and long intergenic non-coding RNAs (lincRNAs: LINC00511, PVT1, MIR4435-2HG, BCYRN1, and MAPKAPK5-AS1) that exhibit oncogenic potential. Taken together, we showed that RGS20 correlates with a few HCC-associated lincRNAs harboring oncogenic potential and is markedly upregulated in HCC patients. Our analysis further supports the putative function of RGS proteins, particularly RGS20, in cancer.
    Type of Medium: Online Resource
    ISSN: 2079-7737
    URL: Article
    DOI: 10.3390/biology11081174
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2661517-4
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  • 3
    Online Resource
    Online Resource
    Crosstalk between β-Catenin and CCL2 Drives Migration of Monocytes towards Glioblastoma Cells
    MDPI AG ; 2022
    In:  International Journal of Molecular Sciences Vol. 23, No. 9 ( 2022-04-20), p. 4562-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 9 ( 2022-04-20), p. 4562-
    Abstract: Isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) is a fast growing and highly heterogeneous tumor, often characterized by the presence of glioblastoma stem cells (GSCs). The plasticity of GSCs results in therapy resistance and impairs anti-tumor immune response by influencing immune cells in the tumor microenvironment (TME). Previously, β-catenin was associated with stemness in GBM as well as with immune escape mechanisms. Here, we investigated the effect of β-catenin on attracting monocytes towards GBM cells. In addition, we evaluated whether CCL2 is involved in β-catenin crosstalk between monocytes and tumor cells. Our analysis revealed that shRNA targeting β-catenin in GBMs reduces monocytes attraction and impacts CCL2 secretion. The addition of recombinant CCL2 restores peripheral blood mononuclear cells (PBMC) migration towards medium (TCM) conditioned by shβ-catenin GBM cells. CCL2 knockdown in GBM cells shows similar effects and reduces monocyte migration to a similar extent as β-catenin knockdown. When investigating the effect of CCL2 on β-catenin activity, we found that CCL2 modulates components of the Wnt/β-catenin pathway and alters the clonogenicity of GBM cells. In addition, the pharmacological β-catenin inhibitor MSAB reduces active β-catenin, downregulates the expression of associated genes and alters CCL2 secretion. Taken together, we showed that β-catenin plays an important role in attracting monocytes towards GBM cells in vitro. We hypothesize that the interactions between β-catenin and CCL2 contribute to maintenance of GSCs via modulating immune cell interaction and promoting GBM growth and recurrence.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms23094562
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 4
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    Online Resource
    PPAR-Responsive Elements Enriched with Alu Repeats May Contribute to Distinctive PPARγ–DNMT1 Interactions in the Genome
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 16 ( 2021-08-07), p. 3993-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 16 ( 2021-08-07), p. 3993-
    Abstract: Background: PPARγ (peroxisome proliferator-activated receptor gamma) is involved in the pathology of numerous diseases, including UM and other types of cancer. Emerging evidence suggests that an interaction between PPARγ and DNMTs (DNA methyltransferase) plays a role in cancer that is yet to be defined. Methods: The configuration of the repeating elements was performed with CAP3 and MAFFT, and the structural modelling was conducted with HDOCK. An evolutionary action scores algorithm was used to identify oncogenic variants. A systematic bioinformatic appraisal of PPARγ and DNMT1 was performed across 29 tumor types and UM available in The Cancer Genome Atlas (TCGA). Results: PPAR-responsive elements (PPREs) enriched with Alu repeats are associated with different genomic regions, particularly the promotor region of DNMT1. PPARγ–DNMT1 co-expression is significantly associated with several cancers. C-terminals of PPARγ and DNMT1 appear to be the potential protein–protein interaction sites where disease-specific mutations may directly impair the respective protein functions. Furthermore, PPARγ expression could be identified as an additional prognostic marker for UM. Conclusions: We hypothesize that the function of PPARγ requires an additional contribution of Alu repeats which may directly influence the DNMT1 network. Regarding UM, PPARγ appears to be an additional discriminatory prognostic marker, in particular in disomy 3 tumors.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13163993
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 5
    Online Resource
    Online Resource
    Mutational Landscape of the BAP1 Locus Reveals an Intrinsic Control to Regulate the miRNA Network and the Binding of Protein Complexes in Uveal Melanoma
    MDPI AG ; 2019
    In:  Cancers Vol. 11, No. 10 ( 2019-10-19), p. 1600-
    Details
    In: Cancers, MDPI AG, Vol. 11, No. 10 ( 2019-10-19), p. 1600-
    Abstract: The BAP1 (BRCA1-associated protein 1) gene is associated with a variety of human cancers. With its gene product being a nuclear ubiquitin carboxy-terminal hydrolase with deubiquitinase activity, BAP1 acts as a tumor suppressor gene with potential pleiotropic effects in multiple tumor types. Herein, we focused specifically on uveal melanoma (UM) in which BAP1 mutations are associated with a metastasizing phenotype and decreased survival rates. We identified the ubiquitin carboxyl hydrolase (UCH) domain as a major hotspot region for the pathogenic mutations with a high evolutionary action (EA) score. This also includes the mutations at conserved catalytic sites and the ones overlapping with the phosphorylation residues. Computational protein interaction studies revealed that distant BAP1-associated protein complexes (FOXK2, ASXL1, BARD1, BRCA1) could be directly impacted by this mutation paradigm. We also described the conformational transition related to BAP1-BRCA-BARD1 complex, which may pose critical implications for mutations, especially at the docking interfaces of these three proteins. The mutations affect - independent of being somatic or germline - the binding affinity of miRNAs embedded within the BAP1 locus, thereby altering the unique regulatory network. Apart from UM, BAP1 gene expression and survival associations were found to be predictive for the prognosis in several (n = 29) other cancer types. Herein, we suggest that although BAP1 is conceptually a driver gene in UM, it might contribute through its interaction partners and its regulatory miRNA network to various aspects of cancer. Taken together, these findings will pave the way to evaluate BAP1 in a variety of other human cancers with a shared mutational spectrum.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers11101600
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2527080-1
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  • 6
    Online Resource
    Online Resource
    Ubiquitin Carboxyl-Terminal Hydrolases (UCHs): Potential Mediators for Cancer and Neurodegeneration
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 11 ( 2020-05-30), p. 3910-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 11 ( 2020-05-30), p. 3910-
    Abstract: Emerging evidence suggests an inverse association between cancer and neurodegenerative diseases (NDD). Although phenotypically different, both diseases display a significant imbalance in the ubiquitination/deubiquitination processes. Therefore, we particularly investigated the expression of ubiquitin C-terminal hydrolases (UCHs: UCH-L1, UCH-L3, UCH-L5 and BAP1), a subfamily of deubiquitinating enzymes (DUBs), using publically available datasets (GTEx, TCGA) and observed altered expression of UCH-L1, UCH-L3, UCH-L5 in 17 cancer types. Interestingly, UCH-L1 (known to be enriched in neurons and interacting with the Parkinson’s disease-associated protein α-synuclein) appeared to be a prognostic indicator of unfavorable outcome in endometrial and urothelial cancer, while increased expression of UCH-L3 and UCH-L5 was associated with poor survival in liver and thyroid cancer, respectively. In normal tissues, UCH-L1 was found to be strongly expressed in the cerebral cortex and hypothalamus, while UCH-L3 expression was somewhat higher in the testis. The occurrence of mutation rates in UCHs also suggests that BAP1 and UCH-L5 may play a more dominant role in cancers than UCH-L1 and UCH-L3. We also characterized the functional context and configuration of the repeat elements in the promoter of DUBs genes and found that UCHs are highly discriminatory for catabolic function and are mainly enriched with LINE/CR1 repeats. Regarding the thesis of an inverse association between cancer and NDD, we observed that among all DUBs, UCHs are the one most involved in both entities. Considering a putative therapeutic potential based on presumed common mechanisms, it will be useful to determine whether other DUBs can compensate for the loss of UCH activity under physiological conditions. However, experimental evidence is required to substantiate this argument.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21113910
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
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  • 7
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    Cytokine-Induced Killer Cells in Combination with Heat Shock Protein 90 Inhibitors Functioning via the Fas/FasL Axis Provides Rationale for a Potential Clinical Benefit in Burkitt’s lymphoma
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 15 ( 2023-08-05), p. 12476-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 15 ( 2023-08-05), p. 12476-
    Abstract: Constant efforts are being made to develop methods for improving cancer immunotherapy, including cytokine-induced killer (CIK) cell therapy. Numerous heat shock protein (HSP) 90 inhibitors have been assessed for antitumor efficacy in preclinical and clinical trials, highlighting their individual prospects for targeted cancer therapy. Therefore, we tested the compatibility of CIK cells with HSP90 inhibitors using Burkitt’s lymphoma (BL) cells. Our analysis revealed that CIK cytotoxicity in BL cells was augmented in combination with independent HSP90 inhibitors 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) and ganetespib. Interestingly, CIK cell cytotoxicity did not diminish after blocking with NKG2D (natural killer group 2, member D), which is a prerequisite for their activation. Subsequent analyses revealed that the increased expression of Fas on the surface of BL cells, which induces caspase 3/7-dependent apoptosis, may account for this effect. Thus, we provide evidence that CIK cells, either alone or in combination with HSP90 inhibitors, target BL cells via the Fas–FasL axis rather than the NKG2D pathway. In the context of clinical relevance, we also found that high expression of HSP90 family genes (HSP90AA1, HSP90AB1, and HSP90B1) was significantly associated with the reduced overall survival of BL patients. In addition to HSP90, genes belonging to the Hsp40, Hsp70, and Hsp110 families have also been found to be clinically significant for BL survival. Taken together, the combinatorial therapy of CIK cells with HSP90 inhibitors has the potential to provide clinical benefits to patients with BL.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms241512476
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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