Glioma stem-like cells evade interferon suppression through MBD3/NuRD complex–mediated STAT1 downregulation

Zhan, Xiaoyan; Guo, Shuang; Li, Yuanyuan; Ran, Haowen; Huang, Haohao; Mi, Lanjuan; Wu, Jin; Wang, Xinzheng; Xiao, Dake; Chen, Li-Shu; Li, Da; Zhang, Songyang; Xu, Yan; Yu, Yu; Li, Tingting; Han, Qin; He, Kun; Cui, Jiuwei; Li, Tao; Zhou, Tao; Rich, Jeremy; Bao, Shideng; Zhang, Xuemin; Li, Ailing; Man, Jianghong

doi:10.1084/jem.20191340

Cited by 39 publications

(31 citation statements)

References 71 publications

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“…IFNs inhibit the tumor-initiating property and expansion of CSCs [ 173 ], and the response to IFNs was suppressed in CSCs to resist the anti-neoplastic effects. The underlying mechanisms remain to be investigated; however, they involve the suppression of autophagy [ 174 ], cyclooxygenase 2, and its product, prostaglandin E2 [ 175 ], as well as the downregulation of LCOR [ 176 ] and IFN signaling molecules [ 173 , 177 ]. Therefore, the two-edged functions of IFNs must be considered in IFN-based cancer therapy.…”

Section: Immunosuppressive Properties Endowed On Cscsmentioning

confidence: 99%

Immune evasion by cancer stem cells

Tsuchiya

Shiota

2021

Regenerative Therapy

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Tumor immunity represents a new avenue for cancer therapy. Immune checkpoint inhibitors have successfully improved outcomes in several tumor types. In addition, currently, immune cell-based therapy is also attracting significant attention. However, the clinical efficacy of these treatments requires further improvement. The mechanisms through which cancer cells escape the immune response must be identified and clarified. Cancer stem cells (CSCs) play a central role in multiple aspects of malignant tumors. CSCs can initiate tumors in partially immunocompromised mice, whereas non-CSCs fail to form tumors, suggesting that tumor initiation is a definitive function of CSCs. However, the fact that non-CSCs also initiate tumors in more highly immunocompromised mice suggests that the immune evasion property may be a more fundamental feature of CSCs rather than a tumor-initiating property. In this review, we summarize studies that have elucidated how CSCs evade tumor immunity and create an immunosuppressive milieu with a focus on CSC-specific characteristics and functions. These profound mechanisms provide important clues for the development of novel tumor immunotherapies.

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Section: Immunosuppressive Properties Endowed On Cscsmentioning

confidence: 99%

Immune evasion by cancer stem cells

Tsuchiya

Shiota

2021

Regenerative Therapy

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“…M1 microglial subtype performs an anti-tumor immune function by producing pro-inflammatory cytokines, ROS, and express signal transducer and activator of transcription 1 (STAT1). In particular, STAT1 plays a key role in cell growth and apoptosis, as it acts as a tumor suppressor by altering the function of protein, DNA, or RNA, or by inducing lipid peroxidation leading to tumor growth inhibition [ 60 , 61 ]. On the contrary, M2 cells are activated by type II cytokines such as IL-4, IL-10, IL-13, and transforming growth factor (TGF)-β, performing a pro-tumor immune response by producing factors as STAT3 [ 62 ], which contribute to tumor proliferation [ 60 , 63 ].…”

Section: Role Of Microglia In Brain Tumorsmentioning

confidence: 99%

Immunomodulatory Effect of Microglia-Released Cytokines in Gliomas

et al. 2021

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Microglia, a type of differentiated tissue macrophage, are considered to be the most plastic cell population of the central nervous system (CNS). Microglia substantially contribute to the growth and invasion of tumor mass in brain tumors including glioblastoma (GB). In response to pathological conditions, resting microglia undergo a stereotypic activation process and become capable of phagocytosis, antigen presentation, and lymphocyte activation. Considering their immune effector function, it is not surprising to see microglia accumulation in almost every CNS disease process, including malignant brain tumors. Large numbers of glioma associated microglia and macrophages (GAMs) can accumulate within the tumor where they appear to have an important role in prognosis. GAMs constitute the largest portion of tumor infiltrating cells, contributing up to 30% of the entire glioma mass and upon interaction with neoplastic cells. GAMs acquire a unique phenotype of activation, including both M1 and M2 specific markers. It has been demonstrated that microglia possess a dual role: on one hand, microglia may represent a CNS anti-tumor response, which is inactivated by local secretion of immunosuppressive factors by glioma cells. On the other hand, taking into account that microglia are capable of secreting a variety of immunomodulatory cytokines, it is possible that they are attracted by gliomas to promote tumor growth. A better understanding of microglia-glioma interaction will be helpful in designing novel immune-based therapies against these fatal tumors. Concluding, as microglia significantly may contribute to glioma biology, favoring tumor growth and invasiveness, these cells represent a valuable alternative/additional target for the development of more effective treatments for gliomas.

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“…Glioma is comprised of heterogeneous cell populations, including a subpopulation of glioma stem cells (GSCs) showing tumor initiation, self-renewal, and multi-lineage differentiation abilities [3]. GSCs have been shown to be responsible for glioma proliferation, therapeutic resistance, and recurrence [4]. There is therefore a great need to identify the molecular mechanisms responsible for GSCs proliferation and progression, as well as to identify novel molecular targets for treatment of glioma.…”

Section: Introductionmentioning

confidence: 99%

The U2AF2 /circRNA ARF1/miR-342–3p/ISL2 feedback loop regulates angiogenesis in glioma stem cells

Jiang

Zhou

Zhao

et al. 2020

J Exp Clin Cancer Res

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Background Glioma is the most common and lethal primary brain tumor in adults, and angiogenesis is one of the key factors contributing to its proliferation, aggressiveness, and malignant transformation. However, the discovery of novel oncogenes and the study of its molecular regulating mechanism based on circular RNAs (circRNAs) may provide a promising treatment target in glioma. Methods Bioinformatics analysis, qPCR, western blotting, and immunohistochemistry were used to detect the expression levels of ISL2, miR-342–3p, circRNA ARF1 (cARF1), U2AF2, and VEGFA. Patient-derived glioma stem cells (GSCs) were established for the molecular experiments. Lentiviral-based infection was used to regulate the expression of these molecules in GSCs. The MTS, EDU, Transwell, and tube formation assays were used to detect the proliferation, invasion, and angiogenesis of human brain microvessel endothelial cells (hBMECs). RNA-binding protein immunoprecipitation, RNA pull-down, dual-luciferase reporter, and chromatin immunoprecipitation assays were used to detect the direct regulation mechanisms among these molecules. Results We first identified a novel transcription factor related to neural development. ISL2 was overexpressed in glioma and correlated with poor patient survival. ISL2 transcriptionally regulated VEGFA expression in GSCs and promoted the proliferation, invasion, and angiogenesis of hBMECs via VEGFA-mediated ERK signaling. Regarding its mechanism of action, cARF1 upregulated ISL2 expression in GSCs via miR-342–3p sponging. Furthermore, U2AF2 bound to and promoted the stability and expression of cARF1, while ISL2 induced the expression of U2AF2, which formed a feedback loop in GSCs. We also showed that both U2AF2 and cARF1 had an oncogenic effect, were overexpressed in glioma, and correlated with poor patient survival. Conclusions Our study identified a novel feedback loop among U2AF2, cARF1, miR-342–3p, and ISL2 in GSCs. This feedback loop promoted glioma angiogenesis, and could provide an effective biomarker for glioma diagnosis and prognostic evaluation, as well as possibly being used for targeted therapy.

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Glioma stem-like cells evade interferon suppression through MBD3/NuRD complex–mediated STAT1 downregulation

Cited by 39 publications

References 71 publications

Immune evasion by cancer stem cells

Immune evasion by cancer stem cells

Immunomodulatory Effect of Microglia-Released Cytokines in Gliomas

The U2AF2 /circRNA ARF1/miR-342–3p/ISL2 feedback loop regulates angiogenesis in glioma stem cells

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