GDF15 promotes glioma stem cell-like phenotype via regulation of ERK1/2–c-Fos–LIF signaling

Zhu, Shan; Yang, Ning; Guan, Yunqian; Wang, Handong; Zang, Guoxia; Lv, Xinping; Deng, Shuanglin; Wang, Wan; Li, Tete; Chen, Jingtao

doi:10.1038/s41420-020-00395-8

Cited by 19 publications

(14 citation statements)

References 51 publications

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“…To investigate the cell source of the two cytokines, we checked literature and analyzed data of the single cell sequencing on GBM by Wang et al 41 . CCL2 was found expressed by GBM cells and macrophages 34 - 37 , but LIF mainly expressed in GBM cells 38 - 40 , which were also supported by single cell sequencing data ( Figure S5 B) . Through immunofluorescence, we found that LIF rarely expressed in macrophages labelled with CD68 ( Figure S5 C) , but highly expressed in GBM cells labelled with Olig2 (Figure 5 B) .…”

Section: Resultssupporting

confidence: 77%

“…IHC result further confirmed high expression of LIF and CCL2 in mGBM1_C compared to mGBM1_A and B (Figure 5 A) . Since CCL2 plays strong chemotaxis function to recruit macrophage and LIF activates STAT3 pathway 34 - 40 , we performed IHC to examine macrophage infiltration using CD86 antibody and activation of STAT3 using p-STAT3 antibody. The data indicated the consistence between CCL2 and CD68, as well as, LIF and p-STAT3 (Figure 5 A) .…”

Section: Resultsmentioning

confidence: 99%

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Comprehensive omics analyses profile genesets related with tumor heterogeneity of multifocal glioblastomas and reveal LIF/CCL2 as biomarkers for mesenchymal subtype

Lv¹,

Fu²,

Yang³

et al. 2022

Theranostics

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Rationale: Around 10%-20% patients with glioblastoma (GBM) are diagnosed with more than one tumor lesions or multifocal GBM (mGBM). However, the understanding on genetic, DNA methylomic, and transcriptomic characteristics of mGBM is still limited. Methods: In this study, we collected nine tumor foci from three mGBM patients followed by whole genome sequencing, whole genome bisulfite sequencing, RNA sequencing, and immunohistochemistry. The data were further examined using public GBM databases and GBM cell line. Results: Analysis on genetic data confirmed common features of GBM, including gain of chr.7 and loss of chr.10, loss of critical tumor suppressors, high frequency of PDGFA and EGFR amplification. Through profiling DNA methylome of individual tumor foci, we found that promoter methylation status of genes involved in detection of chemical stimulus, immune response, and Hippo/YAP1 pathway was significantly changed in mGBM. Although both CNV and promoter methylation alteration were involved in heterogeneity of different tumor foci from same patients, more CNV events than promoter hypomethylation events were shared by different tumor foci, implying CNV were relatively earlier than promoter methylation alteration during evolution of different tumor foci from same mGBM. Moreover, different tumor foci from same mGBM assumed different molecular subtypes and mesenchymal subtype was prevalent in mGBM, which might explain the worse prognosis of mGBM than single GBM. Interestingly, we noticed that LIF and CCL2 was tightly correlated with mesenchymal subtype tumor focus in mGBM and predicted poor survival of GBM patients. Treatment with LIF and CCL2 produced mesenchymal-like transcriptome in GBM cells. Conclusions: Together, our work herein comprehensively profiled multi-omics features of mGBM and emphasized that components of extracellular microenvironment, such as LIF and CCL2, contributed to the evolution and prognosis of tumor foci in mGBM patients.

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Section: Resultssupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

Comprehensive omics analyses profile genesets related with tumor heterogeneity of multifocal glioblastomas and reveal LIF/CCL2 as biomarkers for mesenchymal subtype

Lv¹,

Fu²,

Yang³

et al. 2022

Theranostics

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show abstract

“…Moreover, p53 can regulate maternal reproduction by binding to the intron, located in +873/+898 [ 26 ]. The detailed gene structure of LIF is shown in Figure 1 [ 25 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

Section: Lif and Lif Receptormentioning

confidence: 99%

The Molecular Basis and Therapeutic Potential of Leukemia Inhibitory Factor in Cancer Cachexia

Zeng

Tong

Xiong

2022

Cancers

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Cachexia is a chronic metabolic syndrome that is characterized by sustained weight and muscle mass loss and anorexia. Cachexia can be secondary to a variety of diseases and affects the prognosis of patients significantly. The increase in inflammatory cytokines in plasma is deeply related to the occurrence of cachexia. As a member of the IL-6 cytokine family, leukemia inhibitory factor (LIF) exerts multiple biological functions. LIF is over-expressed in the cancer cells and stromal cells of various tumors, promoting the malignant development of tumors via the autocrine and paracrine systems. Intriguingly, increasing studies have confirmed that LIF contributes to the progression of cachexia, especially in patients with metastatic tumors. This review combines all of the evidence to summarize the mechanism of LIF-induced cachexia from the following four aspects: (i) LIF and cancer-associated cachexia, (ii) LIF and alterations of adipose tissue in cachexia, (iii) LIF and anorexia nervosa in cachexia, and (iv) LIF and muscle atrophy in cachexia. Considering the complex mechanisms in cachexia, we also focus on the interactions between LIF and other key cytokines in cachexia and existing therapeutics targeting LIF.

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“…Apoptosis is a process in which cell death occurs in an orderly manner and is crucial for the maintenance of internal homeostasis ( 64 ). Owing to its reported function as a stress-response protein, GDF15 has been reported to regulate apoptosis ( 65 ). GDF15 is a downstream target of methylseleninic acid (MSA), where GDF15 knockdown significantly inhibited the apoptosis of prostate cancer cells mediated by MSA ( 66 , 67 ).…”

Section: Biological Functions Of Gdf15mentioning

confidence: 99%

Emerging roles of growth differentiation factor‑15 in brain disorders (Review)

Jiang

Zhang

et al. 2021

Exp Ther Med

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Brain disorders, such as Alzheimer's and Parkinson's disease and cerebral stroke, are an important contributor to mortality and disability worldwide, where their pathogenesis is currently a topic of intense research. The mechanisms underlying the development of brain disorders are complex and vary widely, including aberrant protein aggregation, ischemic cell necrosis and neuronal dysfunction. Previous studies have found that the expression and function of growth differentiation factor-15 (GDF15) is closely associated with the incidence of brain disorders. GDF15 is a member of the TGFβ superfamily, which is a dimer-structured stress-response protein. The expression of GDF15 is regulated by a number of proteins upstream, including p53, early growth response-1, non-coding RNAs and hormones. In particular, GDF15 has been reported to serve an important role in regulating angiogenesis, apoptosis, lipid metabolism and inflammation. For example, GDF15 can promote angiogenesis by promoting the proliferation of human umbilical vein endothelial cells, apoptosis of prostate cancer cells and fat metabolism in fasted mice, and GDF15 can decrease the inflammatory response of lipopolysaccharide-treated mice. The present article reviews the structure and biosynthesis of GDF15, in addition to the possible roles of GDF15 in Alzheimer's disease, cerebral stroke and Parkinson's disease. The purpose of the present review is to summarize the mechanism underlying the role of GDF15 in various brain disorders, which hopes to provide evidence and guide the prevention and treatment of these debilitating conditions.

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GDF15 promotes glioma stem cell-like phenotype via regulation of ERK1/2–c-Fos–LIF signaling

Cited by 19 publications

References 51 publications

Comprehensive omics analyses profile genesets related with tumor heterogeneity of multifocal glioblastomas and reveal LIF/CCL2 as biomarkers for mesenchymal subtype

Comprehensive omics analyses profile genesets related with tumor heterogeneity of multifocal glioblastomas and reveal LIF/CCL2 as biomarkers for mesenchymal subtype

The Molecular Basis and Therapeutic Potential of Leukemia Inhibitory Factor in Cancer Cachexia

Emerging roles of growth differentiation factor‑15 in brain disorders (Review)

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