Integration of genome-wide of Stat3 binding and epigenetic modification mapping with transcriptome reveals novel Stat3 target genes in glioma cells

Kruczyk, Marcin; Przanowski, Piotr; Dąbrowski, Michał; Swiatek-Machado, Karolina; Mieczkowski, Jakub; Wallerman, Ola; Ronowicz, Anna; Piotrowski, Arkadiusz; Wadelius, Claes; Kamińska, Bożena; Komorowski, Jan

doi:10.1016/j.bbagrm.2014.07.010

Cited by 16 publications

(10 citation statements)

References 73 publications

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“…ChIP assays were performed on human glioma cells and non-transformed astrocytes as previously described [42, 43]. ChIP was performed with Chip-IT Express Active Motif kit according to manufacturers’ protocol.…”

Section: Methodsmentioning

confidence: 99%

The embryonic type ofSPP1transcriptional regulation is re-activated in glioblastoma

et al. 2016

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Osteopontin (SPP1, a secreted phosphoprotein 1) is primarily involved in immune responses, tissue remodelling and biomineralization. However, it is also overexpressed in many cancers and regulates tumour progression by increasing migration, invasion and cancer stem cell self-renewal. Mechanisms of SPP1 overexpression in gliomas are poorly understood. We demonstrate overexpression of two out of five SPP1 isoforms in glioblastoma (GBM) and differential isoform expression in glioma cell lines. Up-regulated SPP1 expression is associated with binding of the GLI1 transcription factor to the promoter and OCT4 (octamer-binding transcription factor 4) to the first SPP1 intron of the SPP1 gene in human glioma cells but not in non-transformed astrocytes. GLI1 knockdown reduced SPP1 mRNA and protein levels in glioma cells. GLI1 and OCT4 are known regulators of stem cell pluripotency. GBMs contain rare cells that express stem cell markers and display ability to self-renew. We reveal that SPP1 is overexpressed in glioma initiating cells defined by high rhodamine 123 efflux, sphere forming capacity and stemness marker expression. Forced differentiation of human glioma spheres reduced SPP1 expression. Knockdown of SPP1, GLI1 or CD44 with siRNAs diminished sphere formation. C6 glioma cells stably depleted of Spp1 displayed reduced sphere forming capacity and downregulated stemness marker expression. Overexpression of the wild type Spp1, but not Spp1 lacking a Cd44 binding domain, rescued cell ability to form spheres. Our findings show re-activation of the embryonic-type transcriptional regulation of SPP1 in malignant gliomas and point to the importance of SPP1-CD44 interactions in self-renewal and pluripotency glioma initiating cells.

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Section: Methodsmentioning

confidence: 99%

The embryonic type ofSPP1transcriptional regulation is re-activated in glioblastoma

et al. 2016

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“…Studies using manipulation of STAT3 in combination with expression profiling and chromatin profiling and DNA binding assays have identified several hundred STAT3 target genes that vary considerably across different cell types and tissues [67,72–77]. These are not collected in a single repository, however generally genes increased or decreased by STAT3 include those modulating proliferation/survival, pluripotency, angiogenesis, wound healing or invasion/metastasis, and inflammation/immunity In this last class, STAT3 is essential for normal induction of acute phase response (APR) genes in the liver [78,79].…”

Section: Stat3mentioning

confidence: 99%

STAT3 in the systemic inflammation of cancer cachexia

Zimmers

Fishel

Bonetto

2016

Seminars in Cell & Developmental Biology

189

166

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Weight loss is diagnostic of cachexia, a debilitating syndrome contributing mightily to morbidity and mortality in cancer. Most research has probed mechanisms leading to muscle atrophy and adipose wasting in cachexia; however cachexia is a truly systemic phenomenon. Presence of the tumor elicits an inflammatory response and profound metabolic derangements involving not only muscle and fat, but also the hypothalamus, liver, heart, blood, spleen and likely other organs. This global response is orchestrated in part through circulating cytokines that rise in conditions of cachexia. Exogenous Interleukin-6 (IL6) and related cytokines can induce most cachexia symptomatology, including muscle and fat wasting, the acute phase response and anemia, while IL-6 inhibition reduces muscle loss in cancer. Although mechanistic studies are ongoing, certain of these cachexia phenotypes have been causally linked to the cytokine-activated transcription factor, STAT3, including skeletal muscle wasting, cardiac dysfunction and hypothalamic inflammation. Correlative studies implicate STAT3 in fat wasting and the acute phase response in cancer cachexia. Parallel data in non-cancer models and disease states suggest both contributory and protective functions for STAT3 in other organs during cachexia. Finally, STAT3 contributes to cancer cachexia through enhancing tumorigenesis, metastasis and immune suppression, particularly in tumors associated with high prevalence of cachexia. This review examines the evidence linking STAT3 to multi-organ manifestations of cachexia in cancer and evidence for targeting STAT3 for anti-cachexia therapies.

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“…STAT3 is an important member of JAK‐STAT signaling pathway and is a latent transcription factor which can be activated by phosphorylation (Kruczyk et al, ; Scholz et al, ). It is increased in many cancers and can play important roles in regulating various genes (Toyonaga et al, ; Yao et al, ).…”

Section: Introductionmentioning

confidence: 99%

H19 promotes non‐small‐cell lung cancer (NSCLC) development through STAT3 signaling via sponging miR‐17

Huang

Lei

et al. 2018

Journal Cellular Physiology

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LncRNAs can exhibit crucial roles in the development of multiple cancers, including non-small cell lung cancer (NSCLC). Currently, we investigated the role of lncRNA H19 in NSCLC. In our study, it was found that H19 was upregulated in A549 and H1299 cells compared to normal lung epithelial BEAS-2B cells. Meanwhile, we observed that miR-17 was downregulated in NSCLC cell lines. Inhibited H19 can suppress the growth, migration, and invasion of NSCLC cells and bioinformatics search was performed to predict the correlation between H19 and miR-17. Overexpression of miR-17 was able to inhibit the progression of NSCLC cells while reversely miR-17 inhibitors reversed this process. In addition, signal transducers and activators of transcription (STAT3), as an mRNA target of miR-17, was presented in our research. Moreover, we discovered that H19 demonstrated its biological functions via regulating miR-17 and STAT3 in vitro. Silencing H19 greatly increased STAT3 expression by sponging miR-19 in vitro. It was hypothesized that H19 may serve as a competing endogenous RNA (ceRNA) to modulate STAT3 by attaching miR-17 in lung cancer. In summary, our findings indicated that H19/miR-17/STAT3 axis participated in NSCLC development. H19 could be regarded as a significant prognostic biomarker in NSCLC progression.

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Integration of genome-wide of Stat3 binding and epigenetic modification mapping with transcriptome reveals novel Stat3 target genes in glioma cells

Cited by 16 publications

References 73 publications

The embryonic type ofSPP1transcriptional regulation is re-activated in glioblastoma

The embryonic type ofSPP1transcriptional regulation is re-activated in glioblastoma

STAT3 in the systemic inflammation of cancer cachexia

H19 promotes non‐small‐cell lung cancer (NSCLC) development through STAT3 signaling via sponging miR‐17

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