IL-4/Stat6 activities correlate with apoptosis and metastasis in colon cancer cells

Li, Ben Hui; Yang, Xian; Li, Pin Dong; Qin, Yuan; Liu, Xiao Hong; Yuan, Jia; Zhang, Wen Jie

doi:10.1016/j.bbrc.2008.02.052

Cited by 79 publications

(78 citation statements)

References 23 publications

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“…In contrast to our results, previous reports indicated that IL-4-induced STAT6 represses COX-2 in human follicular dendritic cells (53), and unphosphorylated STAT6 contributes to constitutive COX-2 expression in lung cancer (54). STAT6 is overexpressed in several human malignancies, including prostate and colon cancer, lymphoma, leukemia, and glioma (16,55,56). In such cells, STAT6 induces resistance to apoptosis, resulting in cancer cell growth and increased tissue invasiveness.…”

Section: Discussioncontrasting

confidence: 99%

Astrocytes, but Not Microglia, Rapidly Sense H2O2 via STAT6 Phosphorylation, Resulting in Cyclooxygenase-2 Expression and Prostaglandin Release

Park

Lee

Kim

et al. 2012

The Journal of Immunology

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Emerging evidence has established that astrocytes, once considered passive supporting cells that maintained extracellular ion levels and served as a component of the blood–brain barrier, play active regulatory roles during neurogenesis and in brain pathology. In the current study, we demonstrated that astrocytes sense H2O2 by rapidly phosphorylating the transcription factor STAT6, a response not observed in microglia. STAT6 phosphorylation was induced by generators of other reactive oxygen species (ROS) and reactive nitrogen species, as well as in the reoxygenation phase of hypoxia/reoxygenation, during which ROS are generated. Src–JAK pathways mediated STAT6 phosphorylation upstream. Experiments using lipid raft disruptors and analyses of detergent-fractionated cells demonstrated that H2O2-induced STAT6 phosphorylation occurred in lipid rafts. Under experimental conditions in which H2O2 did not affect astrocyte viability, H2O2-induced STAT6 phosphorylation resulted in STAT6-dependent cyclooxygenase-2 expression and subsequent release of PGE2 and prostacyclin, an effect also observed in hypoxia/reoxygenation. Finally, PGs released from H2O2-stimulated astrocytes inhibited microglial TNF-α expression. Accordingly, our results indicate that ROS-induced STAT6 phosphorylation in astrocytes can modulate the functions of neighboring cells, including microglia, through cyclooxygenase-2 induction and subsequent release of PGs. Differences in the sensitivity of STAT6 in astrocytes (highly sensitive) and microglia (insensitive) to phosphorylation following brief exposure to H2O2 suggest that astrocytes can act as sentinels for certain stimuli, including H2O2 and ROS, refining the canonical notion that microglia are the first line of defense against external stimuli.

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Section: Discussioncontrasting

confidence: 99%

Astrocytes, but Not Microglia, Rapidly Sense H2O2 via STAT6 Phosphorylation, Resulting in Cyclooxygenase-2 Expression and Prostaglandin Release

Park

Lee

Kim

et al. 2012

The Journal of Immunology

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“…Total and activated STAT6 were more abundant in KM12SM cells, with no significant differences in STAT3. High levels of STAT6 in colon cancer cells have been associated to high invasiveness/metastasis (15). These results support a potential action of IL-4 and IL-13 on KM12 cells.…”

Section: Resultssupporting

confidence: 68%

High Expression of IL-13 Receptor α2 in Colorectal Cancer Is Associated with Invasion, Liver Metastasis, and Poor Prognosis

et al. 2012

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Autocrine secretion of cytokines by metastatic colorectal cancer cells and their role during invasion and liver homing has been poorly characterized. In this study, we used cytokine arrays to analyze the secretomes of poorly and highly metastatic colorectal cancer cells. Compared with poorly metastatic cancer cells, highly metastatic cells expressed increased levels of the immunosuppressive cytokines interleukin (IL)-4 and IL-13 in addition to increased surface expression of the high affinity IL-13 receptor IL-13Ra2, suggesting that IL-13Ra2 mediates IL-13 effects in colorectal cancer cells. Silencing of IL-13Ra2 in highly metastatic cells led to a decrease in adhesion capacity in vitro and a reduction in liver homing and increased survival in vivo, revealing a role for this receptor in cell adhesion, migration, invasion, and metastatic colonization. In support of this, IL-13 signaling activated the oncogenic signaling molecules phosphoinositide 3-kinase, AKT, and SRC in highly metastatic cells. Clinically, high expression of IL-13Ra2 was associated with later stages of disease progression and poor outcome in patients with colorectal cancer. Our findings therefore support a critical role for IL-13Ra2 expression in colon cancer invasion and metastasis. Cancer Res; 72(11); 2780-90. Ó2012 AACR.

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“…20 The oncogenic roles have been also assigned to STAT5 21 and STAT6. 22 In our study, we assessed the levels of selected STAT proteins and their inhibitors using the quantitative ELISA in NSCLC tissue samples. This method provides enhanced specificity and generates numerical results amenable to an objective and consistent interpretation.…”

Section: 16mentioning

confidence: 99%

Immunoexpression analysis of selected JAK/STAT pathway molecules in non-small cell lung cancer patients

Pastuszak-Lewandoska¹,

Domańska-Senderowska²,

Kordiak³

et al. 2017

Polish Archives of Internal Medicine

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IL-4/Stat6 activities correlate with apoptosis and metastasis in colon cancer cells

Cited by 79 publications

References 23 publications

Astrocytes, but Not Microglia, Rapidly Sense H2O2 via STAT6 Phosphorylation, Resulting in Cyclooxygenase-2 Expression and Prostaglandin Release

Astrocytes, but Not Microglia, Rapidly Sense H2O2 via STAT6 Phosphorylation, Resulting in Cyclooxygenase-2 Expression and Prostaglandin Release

High Expression of IL-13 Receptor α2 in Colorectal Cancer Is Associated with Invasion, Liver Metastasis, and Poor Prognosis

Immunoexpression analysis of selected JAK/STAT pathway molecules in non-small cell lung cancer patients

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