TGF-β Signaling Promotes Glioma Progression Through Stabilizing Sox9

Liu, Nan; Sun, Zhi-Chuan; Jiang, Yongli; Jiang, Tongtong; Xv, Meng; Jia, Lintao; Tu, Yanyang; Wang, Liang

doi:10.3389/fimmu.2020.592080

Cited by 24 publications

(22 citation statements)

References 33 publications

(38 reference statements)

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“…The related mechanism and therapeutic strategies have been gradually clarified. It has already been found that the high proliferation and invasion of gliomas and the poor prognosis in glioma patients are usually accompanied by SMAD signaling in early studies, and Sox9 becomes an important regulatory target when TGF-β works in glioma progression [ 212 , 213 ]. TGF-β plays an essential role in glioma progression by inducing the proliferation, invasion, EMT, and migration of glioma cells and depressing immune effector cells [ 214 – 216 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting TGF-β signal transduction for fibrosis and cancer therapy

et al. 2022

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Transforming growth factor β (TGF-β) has long been identified with its intensive involvement in early embryonic development and organogenesis, immune supervision, tissue repair, and adult homeostasis. The role of TGF-β in fibrosis and cancer is complex and sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage of the disease. Under pathological conditions, overexpressed TGF-β causes epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition, cancer-associated fibroblast (CAF) formation, which leads to fibrotic disease, and cancer. Given the critical role of TGF-β and its downstream molecules in the progression of fibrosis and cancers, therapeutics targeting TGF-β signaling appears to be a promising strategy. However, due to potential systemic cytotoxicity, the development of TGF-β therapeutics has lagged. In this review, we summarized the biological process of TGF-β, with its dual role in fibrosis and tumorigenesis, and the clinical application of TGF-β-targeting therapies.

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Section: Introductionmentioning

confidence: 99%

Targeting TGF-β signal transduction for fibrosis and cancer therapy

et al. 2022

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“…8D). A tendency towards enhanced β-catenin and SMAD2/3 activity, known mediators of stem cell maintenance and proliferation following TMZ treatment (21), was detected in shPPP2R5E tumors, whereas expression of SOX9, a protein involved in differentiation, migration and invasion of GBM (22), was reduced (Fig. 8D).…”

Section: Resultsmentioning

confidence: 98%

Unlocking the potential ofmiR-19bin the regulation of temozolomide response in glioblastoma patients via targeting PPP2R5E, a subunit of the protein phosphatase 2A complex

Kashani

Hlavačková

Haemmig

et al. 2023

Preprint

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Despite standard of care, glioblastoma IDH wt (GBM) inevitably recur accentuating the need to elucidate mechanisms of therapy resistance. The DNA alkylating agent temozolomide (TMZ) triggers futile DNA mismatch repair cycles and persistent DNA double strand breaks, but tumors counteract this genotoxic stress by inducing DNA damage repair and survival pathways. GBM cells overexpressing miR-19b-3p were reproducibly selected by TMZ treatment in systematic lentiviral microRNA screens, a finding that was investigated mechanistically. Attenuation of miR-19b in glioblastoma cell lines and primary glioblastoma stem cells (GSCs) induced DNA damage as indicated by enhanced CHK1 and CHK2 phosphorylation, gH2AX foci formation, and senescence. These phenotypes were further enhanced by TMZ treatment. Enhanced expression of miR-19b in GBM tissues was associated with downregulation of regulatory subunit PPP2R5E of Ser/Thr phosphatase PP2A in the mesenchymal subtype of GBM in agreement with miR-19b targeting PPP2R5E. Knocking down PPP2R5E antagonized the phenotypes elicited by miR-19b attenuation, and these effects were reversed in miR-19b attenuated/PPP2R5E knockdown cells suggesting a role of the miR-19b/PPP2R5E axis in TMZ-induced DNA damage response. In agreement with PP2A reactivation by miR-19b attenuation, PP2A activating drug, FTY720, or knocking down endogenous PP2A inhibiting proteins (PAIP), acted synergistically with TMZ to induce cell death. Enhanced TMZ resistance elicited by knocking down PPP2R5E was confirmed in orthotopic mouse GSC xenografts. These results provide insights in TMZ resistance mechanisms of GBM elicited by PPP2R5E targeting of miR-19b. Attenuation of miR-19b or PPP2R5E expression could potentially be exploited in adjuvant therapy of GBM.

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“…Ultimately, this model highlights that the presence of human stem cell derived microglial cells with human glioma cells results in not only larger tumors but also an upregulation of genes similar to those known to be upregulated in certain gliomas ( 40 – 45 ). Recent findings have begun to shed light on how GBM can use microglia to induce immunosuppression within the tumor microenvironment.…”

Section: Cell Lines and Mouse Models Of Gliomamentioning

confidence: 92%

Pre-clinical models for evaluating glioma targeted immunotherapies

Frederico

Zhang²,

Hu³

et al. 2023

Front. Immunol.

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Gliomas have an extremely poor prognosis in both adult and pediatric patient populations as these tumors are known to grow aggressively and respond poorly to standard of care treatment. Currently, treatment for gliomas involves surgical resection followed by chemoradiation therapy. However, some gliomas, such as diffuse midline glioma, have more limited treatment options such as radiotherapy alone. Even with these interventions, the prognosis for those diagnosed with a glioma remains poor. Immunotherapy is highly effective for some cancers and there is great interest in the development of effective immunotherapies for the treatment of gliomas. Clinical trials evaluating the efficacy of immunotherapies targeted to gliomas have largely failed to date, and we believe this is partially due to the poor choice in pre-clinical mouse models that are used to evaluate these immunotherapies. A key consideration in evaluating new immunotherapies is the selection of pre-clinical models that mimic the glioma-immune response in humans. Multiple pre-clinical options are currently available, each one with their own benefits and limitations. Informed selection of pre-clinical models for testing can facilitate translation of more promising immunotherapies in the clinical setting. In this review we plan to present glioma cell lines and mouse models, as well as alternatives to mouse models, that are available for pre-clinical glioma immunotherapy studies. We plan to discuss considerations of model selection that should be made for future studies as we hope this review can serve as a guide for investigators as they choose which model is best suited for their study.

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TGF-β Signaling Promotes Glioma Progression Through Stabilizing Sox9

Cited by 24 publications

References 33 publications

Targeting TGF-β signal transduction for fibrosis and cancer therapy

Targeting TGF-β signal transduction for fibrosis and cancer therapy

Unlocking the potential ofmiR-19bin the regulation of temozolomide response in glioblastoma patients via targeting PPP2R5E, a subunit of the protein phosphatase 2A complex

Pre-clinical models for evaluating glioma targeted immunotherapies

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