STAT1β enhances STAT1 function by protecting STAT1α from degradation in esophageal squamous cell carcinoma

Zhang, Ying; Chen, Yelong; Yun, Hailong; Liu, Zhaoyong; Shu, Min; Lai, Raymond

doi:10.1038/cddis.2017.481

Cited by 21 publications

(23 citation statements)

References 26 publications

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“…We cannot completely rule out other mechanisms that can result in the STAT1 increase in the AGS cell line by ADAR1 knockdown. For example, a recent study showed that STAT1β can enhance STAT1 function by protecting STAT1α from degradation in esophageal squamous cell carcinoma [ 31 ]. STAT1β, a naturally spliced isoform of STAT1, lacks a 38-amino acid segment that includes the conserved STAT1 S727 phosphorylation site and most of the C-terminal transactivation domain [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

ADAR1 Suppresses Interferon Signaling in Gastric Cancer Cells by MicroRNA-302a-Mediated IRF9/STAT1 Regulation

Jiang

Park

Cho

et al. 2020

IJMS

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ADAR (adenosine deaminase acting on RNA) catalyzes the deamination of adenosine to generate inosine, through its binding to double-stranded RNA (dsRNA), a phenomenon known as RNA editing. One of the functions of ADAR1 is suppressing the type I interferon (IFN) response, but its mechanism in gastric cancer is not clearly understood. We analyzed changes in RNA editing and IFN signaling in ADAR1-depleted gastric cancer cells, to clarify how ADAR1 regulates IFN signaling. Interestingly, we observed a dramatic increase in the protein level of signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factor 9 (IRF9) upon ADAR1 knockdown, in the absence of type I or type II IFN treatment. However, there were no changes in protein expression or localization of the mitochondrial antiviral signaling protein (MAVS) and interferon alpha and beta-receptor subunit 2 (IFNAR2), the two known mediators of IFN production. Instead, we found that miR-302a-3p binds to the untranslated region (UTR) of IRF9 and regulate its expression. The treatment of ADAR1-depleted AGS cells with an miR-302a mimic successfully restored IRF9 as well as STAT1 protein level. Hence, our results suggest that ADAR1 regulates IFN signaling in gastric cancer through the suppression of STAT1 and IRF9 via miR-302a, which is independent from the RNA editing of known IFN production pathway.

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Section: Discussionmentioning

confidence: 99%

ADAR1 Suppresses Interferon Signaling in Gastric Cancer Cells by MicroRNA-302a-Mediated IRF9/STAT1 Regulation

Jiang

Park

Cho

et al. 2020

IJMS

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“…STAT3 and STAT1 transcriptional activity analyses were performed. Transcription activity was measured by a luciferase reporter gene assay, 12 using the Dual-Luciferase reporter assay system according to the manufacturer’s instructions (Promega Corporation, Madison, WI, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Nuclear and cytoplasmic protein of ESCC cells was extracted using an NE-PER protein extraction kit (Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer’s instructions as described previously. 12 Oligonucleotide pull-down assays were performed with an annealed nucleotide comprising the STAT3 or STAT1 consensus site with a biotin label.…”

Section: Methodsmentioning

confidence: 99%

STAT1 inhibits STAT3 activation in esophageal squamous cell carcinoma

Liu¹,

Zhang²,

Chen³

et al. 2018

CMAR

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BackgroundSignal transducer and activator of transcription (STAT) 1 is an important transcription factor and has been reported to be a tumor suppressor in many types of cancer. However, another STAT family member, STAT3, is considered to be an oncogene. The cross-talk between STAT1 and STAT3 in cancer has not been fully demonstrated.Materials and methodsEsophageal squamous cell carcinoma (ESCC) was used as a model to examine STAT1-STAT3 cross-regulation in cancer. We detected STAT1-STAT3 binding by co-immunoprecipitation (co-IP) and measured the transcription activity by using a luciferase reporter gene. DNA binding was detected by a DNA probe. Expression of STAT1 and STAT3 in ESCC was detected by immunohistochemistry.ResultsWe found that STAT1 attenuated STAT3 activity upon oncostatin M treatment by decreasing STAT3 transcription activity and DNA binding ability of STAT3. Furthermore STAT3 downregulation increased the phosphorylation and transcriptional activation of STAT1. Finally, STAT1 expression and STAT3 expression were negatively correlated in ESCC cases.ConclusionAltogether, this paper demonstrated STAT1 and STAT3 cross-regulation in ESCC and proposed that STAT3 downregulation and/or STAT1 accumulation may be a therapeutic approach to treat ESCC.

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“…IHC staining was performed using the EnVision System using peroxidase labeling (Dako, Carpinteria, CA) as described previously [11]. IHC staining was examined by two pathologists who were blinded to the clinical outcome.…”

Section: Immunohistochemistry (Ihc)mentioning

confidence: 99%

“…Nuclear and cytoplasmic extraction and western blot analysis NE-PER TM nuclear and cytoplasmic extraction reagents (Thermo Scienti c, MA, USA) were used to separate and prepare cytoplasmic and nuclear extracts from ESCC cells. Western blotting was performed as described previously [11]. Antibodies against human β-actin, MAP2K3, p-MAP2K3, EGFR, p-EGFR, STAT1, p-STAT1, STAT3, p-STAT3, caspase 3, cleaved(cl-) caspase 3, GFP, Ki67, Flag, Ub, HA, MDM5, cleaved(cl-) PARP were purchased from Cell Signaling Technology (MA, USA).…”

Section: Introductionmentioning

confidence: 99%

The miR-19b-3p/MAP2K3/STAT3 Feedback Loop Regulates Cell Proliferation and Invasion in Esophageal Squamous Cell Carcinoma

Zhang¹,

Liu²,

Lu³

et al. 2020

Preprint

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Background Esophageal squamous cell carcinoma (ESCC) remains one of the most refractory malignancies worldwide. MAP2K3 has been reported to play an important role in tumor progression. However, whether MAP2K3 also affects ESCC remains to be determined. Method We used a CRISPR/Cas9 kinome screen to identify the genes related to ESCC cell survival. The MAP2K3 expression was detected in ESCC tissues by immunohistochemistry and westernblot. The function of MAP2K3 in ESCC was investigated using colony formation assay and Transwell assay in vivo and in vitro. RNA sequence was performed to verify its downstream signaling pathways. DNA binding of the gene promoter region was detected by chromatin immunoprecipitation.Result Downregulation of MAP2K3 was found in ESCC and correlated with clinically poor survival. MAP2K3 inhibited cell proliferation and invasion via the EGFR/STAT3 signaling pathway in ESCC cells. MAP2K3 suppressed STAT3 expression and activation by interacting with MDM2 to promote the ubiquitin proteasome degradation of STAT3. Furthermore, MAP2K3 was a downstream target of miR-19b-3p, which promoted ESCC tumorigenesis. STAT3 binds to the MIR19B promoter region to increase the expression of miR-19b-3p in ESCC cells. Conclusion In summary, our results demonstrated that the miR-19b-3p/MAP2K3/STAT3 feedback loop regulates tumorigenesis in ESCC and elucidate the potential of therapeutically targeting this pathway in ESCC.

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STAT1β enhances STAT1 function by protecting STAT1α from degradation in esophageal squamous cell carcinoma

Cited by 21 publications

References 26 publications

ADAR1 Suppresses Interferon Signaling in Gastric Cancer Cells by MicroRNA-302a-Mediated IRF9/STAT1 Regulation

ADAR1 Suppresses Interferon Signaling in Gastric Cancer Cells by MicroRNA-302a-Mediated IRF9/STAT1 Regulation

STAT1 inhibits STAT3 activation in esophageal squamous cell carcinoma

The miR-19b-3p/MAP2K3/STAT3 Feedback Loop Regulates Cell Proliferation and Invasion in Esophageal Squamous Cell Carcinoma

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