Autocrine IL6-Mediated Activation of the STAT3–DNMT Axis Silences the TNFα–RIP1 Necroptosis Pathway to Sustain Survival and Accumulation of Myeloid-Derived Suppressor Cells

Smith, Alyssa D.; Lu, Chunwan; Payne, Daniela; Paschall, Amy V.; Klement, John D.; Redd, Priscilla S.; Ibrahim, Mohammed L.; Yang, Dafeng; Han, Qimei; Shi, Huidong; Hartney, Thomas J.; Nayak-Kapoor, Asha; Liu, Kebin

doi:10.1158/0008-5472.can-19-3670

Cited by 54 publications

(35 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This demonstrates that necroptosis may be positive in esophageal cancer through regulating cisplatin sensitivity and inducing cell necrosis. There is accumulating evidence of the induction of cellular necroptosis involving STAT3 function of transcription [ 60 , 61 , 62 ]. In our study, we found high STAT3β expression contributed to cellular necroptosis and cell cycle arrest after CCRT ( Figure 5 A,B).…”

Section: Discussionmentioning

confidence: 99%

STAT3β Enhances Sensitivity to Concurrent Chemoradiotherapy by Inducing Cellular Necroptosis in Esophageal Squamous Cell Carcinoma

Zheng

Yang

Luo

et al. 2021

Cancers

View full text Add to dashboard Cite

Concurrent chemoradiotherapy (CCRT), especially platinum plus radiotherapy, is considered to be one of the most promising treatment modalities for patients with advanced esophageal cancer. STAT3β regulates specific target genes and inhibits the process of tumorigenesis and development. It is also a good prognostic marker and a potential marker for response to adjuvant chemoradiotherapy (ACRT). We aimed to investigate the relationship between STAT3β and CCRT. We examined the expression of STAT3α and STAT3β in pretreatment tumor biopsies of 105 ESCC patients who received CCRT by immunohistochemistry. The data showed that ESCC patients who demonstrate both high STAT3α expression and high STAT3β expression in the cytoplasm have a significantly better survival rate, and STAT3β expression is an independent protective factor (HR = 0.424, p = 0.003). Meanwhile, ESCC patients with high STAT3β expression demonstrated a complete response to CCRT in 65 patients who received platinum plus radiation therapy (p = 0.014). In ESCC cells, high STAT3β expression significantly inhibits the ability of colony formation and cell proliferation, suggesting that STAT3β enhances sensitivity to CCRT (platinum plus radiation therapy). Mechanistically, through RNA-seq analysis, we found that the TNF signaling pathway and necrotic cell death pathway were significantly upregulated in highly expressed STAT3β cells after CCRT treatment. Overall, our study highlights that STAT3β could potentially be used to predict the response to platinum plus radiation therapy, which may provide an important insight into the treatment of ESCC.

show abstract

Section: Discussionmentioning

confidence: 99%

STAT3β Enhances Sensitivity to Concurrent Chemoradiotherapy by Inducing Cellular Necroptosis in Esophageal Squamous Cell Carcinoma

Zheng

Yang

Luo

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…The phenotype and activity of BM-derived MDSCs depends on transcription factor C/EBPβ( Marigo et al, 2010 ). IL-6-mediated activation of STAT3 also sustains survival and accumulation of MDSCs( Smith et al, 2020 ). Our results showed that HT can inhibit the transcription of C/EBPβ, and inhibit the protein expression of C/EBPβ ( Figures 4F,I,J ).…”

Section: Resultsmentioning

confidence: 99%

Hydroxytyrosol Inhibits MDSCs and Promotes M1 Macrophages in Mice With Orthotopic Pancreatic Tumor

Wang

Yang

et al. 2021

Front. Pharmacol.

View full text Add to dashboard Cite

The poor immunotherapy of pancreatic cancer is mainly due to its complex immunosuppressive microenvironment. The Mediterranean diet contributes to low cancer incidence. Hydroxytyrosol (HT) derived from olive oil has multiple health-promoting effects, but its therapeutic effect on pancreatic cancer remains controversial. Here, we evaluated the inhibitory effect of HT on mouse pancreatic cancer, and the effect of HT on the immune microenvironment. We found that HT can inhibit the proliferation of Panc 02 cells through signal transducer and activator of transcription (STAT) 3/Cyclin D1 signaling pathway. In the tumor-bearing mice treated with HT, the orthotopic pancreatic tumors were suppressed, accompanied by a decrease in the proportion of myeloid-derived suppressor cells (MDSCs) and an increase in the proportion of M1 macrophages. In addition, we found that HT inhibited the expression of immunosuppressive molecules in bone marrow (BM)-derived MDSCs, as well as down-regulated CCAAT/enhancer-binding protein beta (C/EBPβ) and phosphorylation of STAT3. Moreover, HT enhanced the anti-tumor effect of anti-CD47 antibody in vivo. HT combined with plumbagin (PLB) induced more Panc 02 cells death than HT or PLB alone. This combination therapy not only inhibited the accumulation of MDSCs, but also promoted the infiltration of CD4+ and CD8+ T cells in the tumors. In summary, HT is a potential immunomodulatory drug for the treatment of pancreatic cancer.

show abstract

“…TNFα mediated necroptosis is one type of necroptosis cell death in many diseases, such as glioma cells 37 and alveolar epithelial cells 38 . TNFα can also induce necroptosis of inflammatory cells by activating RIP1 and RIP3 39 . Activation of RIP3 induced necroptosis of renal tubular epithelial cells, knockdown of RIP3 reduced the degree of renal injury, and inhibition of Caspase8 also induced necroptosis in renal tubular epithelial cells 17 .…”

Section: Discussionmentioning

confidence: 99%

MiR-124 Negatively Regulated PARP1 to Alleviate Renal Ischemia-reperfusion Injury by Inhibiting TNFα/RIP1/RIP3 Pathway

Ke¹,

Zhao²,

Luo³

et al. 2021

Int. J. Biol. Sci.

View full text Add to dashboard Cite

Renal ischemia-reperfusion injury (IRI) is one of the underlying causes of acute kidney injury and also an unavoidable problem in renal transplantation. Lots of miRNAs and targets have been found to participate in some post-transcriptional processes in renal IRI, however, the detailed knowledge of miRNA targets and mechanism is unknown. In this study, miR-124 was found inhibited and PARP1 was overexpressed in renal IRI cells and mouse models. Dual-luciferase reporter assay revealed that miR-124 post-transcriptionally regulated PAPR1 3′UTR activity. Our results also demonstrated miR-124 negatively regulated PARP1 which played a role in necroptosis of renal ischemia-reperfusion injury by activating TNFα. TNFα induced the RIP1/RIP3 necroptosis signaling pathway to aggravate the renal injury. Collectively, these studies identified PARP1 as a direct target of miR-124 and activated RIP1/RIP3 necroptosis signaling pathway through TNFα. It elucidated the protective effect of miR-124 in renal ischemia-reperfusion injury, which demonstrated the regulatory mechanism of miR-124/PARP1 in renal injury and exhibited the potential as a novel therapeutic for the treatment of renal IRI.

show abstract

Autocrine IL6-Mediated Activation of the STAT3–DNMT Axis Silences the TNFα–RIP1 Necroptosis Pathway to Sustain Survival and Accumulation of Myeloid-Derived Suppressor Cells

Cited by 54 publications

References 50 publications

STAT3β Enhances Sensitivity to Concurrent Chemoradiotherapy by Inducing Cellular Necroptosis in Esophageal Squamous Cell Carcinoma

STAT3β Enhances Sensitivity to Concurrent Chemoradiotherapy by Inducing Cellular Necroptosis in Esophageal Squamous Cell Carcinoma

Hydroxytyrosol Inhibits MDSCs and Promotes M1 Macrophages in Mice With Orthotopic Pancreatic Tumor

MiR-124 Negatively Regulated PARP1 to Alleviate Renal Ischemia-reperfusion Injury by Inhibiting TNFα/RIP1/RIP3 Pathway

Contact Info

Product

Resources

About