scholarly journals Activation of the STAT3 Signaling Pathway by the RNA-Dependent RNA Polymerase Protein of Arenavirus

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 976
Author(s):  
Qingxing Wang ◽  
Qilin Xin ◽  
Weijuan Shang ◽  
Weiwei Wan ◽  
Gengfu Xiao ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Signaling Pathway ◽  
Cell Biology ◽  
A549 Cells ◽  
Hemorrhagic Fever ◽  
Lymphocytic Choriomeningitis ◽  
Rna Dependent Rna Polymerase ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Transcription 3

Arenaviruses cause chronic and asymptomatic infections in their natural host, rodents, and several arenaviruses cause severe hemorrhagic fever that has a high mortality in infected humans, seriously threatening public health. There are currently no FDA-licensed drugs available against arenaviruses; therefore, it is important to develop novel antiviral strategies to combat them, which would be facilitated by a detailed understanding of the interactions between the viruses and their hosts. To this end, we performed a transcriptomic analysis on cells infected with arenavirus lymphocytic choriomeningitis virus (LCMV), a neglected human pathogen with clinical significance, and found that the signal transducer and activator of transcription 3 (STAT3) signaling pathway was activated. A further investigation indicated that STAT3 could be activated by the RNA-dependent RNA polymerase L protein (Lp) of LCMV. Our functional analysis found that STAT3 cannot affect LCMV multiplication in A549 cells. We also found that STAT3 was activated by the Lp of Mopeia virus and Junin virus, suggesting that this activation may be conserved across certain arenaviruses. Our study explored the interactions between arenaviruses and STAT3, which may help us to better understand the molecular and cell biology of arenaviruses.

scholarly journals KDM3A histone demethylase functions as an essential factor for activation of JAK2−STAT3 signaling pathway

2018 ◽  
Vol 115 (46) ◽  
pp. 11766-11771 ◽  
Author(s):  
Hyunkyung Kim ◽  
Dongha Kim ◽  
Seon Ah Choi ◽  
Chang Rok Kim ◽  
Se Kyu Oh ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Therapeutic Strategy ◽  
Transcriptional Coactivator ◽  
Essential Factor ◽  
Stat3 Signaling ◽  
Lysine Specific Demethylase ◽  
Tyrosine Kinase 2 ◽  
Stat3 Signaling Pathway ◽  
Janus Tyrosine Kinase 2 ◽  
Transcription 3

Janus tyrosine kinase 2 (JAK2)−signal transducer and activator of transcription 3 (STAT3) signaling pathway is essential for modulating cellular development, differentiation, and homeostasis. Thus, dysregulation of JAK2−STAT3 signaling pathway is frequently associated with human malignancies. Here, we provide evidence that lysine-specific demethylase 3A (KDM3A) functions as an essential epigenetic enzyme for the activation of JAK2−STAT3 signaling pathway. KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2−KDM3A signaling cascade induced by IL-6 leads to alteration of histone H3K9 methylation as a predominant epigenetic event, thereby providing the functional and mechanistic link between activation of JAK2−STAT3 signaling pathway and its epigenetic control. Together, our findings demonstrate that inhibition of KDM3A phosphorylation could be a potent therapeutic strategy to control oncogenic effect of JAK2−STAT3 signaling pathway.

scholarly journals 3-Formylchromone Counteracts STAT3 Signaling Pathway by Elevating SHP-2 Expression in Hepatocellular Carcinoma

Biology ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 29
Author(s):  
Chakrabhavi Dhananjaya Mohan ◽  
Min Hee Yang ◽  
Shobith Rangappa ◽  
Arunachalam Chinnathambi ◽  
Sulaiman Ali Alharbi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Tyrosine Kinases ◽  
Present Report ◽  
Migration And Invasion ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Substantial Toxicity ◽  
Transcription 3 ◽  
Constitutive Phosphorylation

Hepatocellular carcinoma (HCC) is one of the leading cancers that contribute to a large number of deaths throughout the globe. The signal transducer and activator of transcription 3 (STAT3) is a tumorigenic protein that is overactivated in several human malignancies including HCC. In the present report, the effect of 3-formylchromone (3FC) on the STAT3 signaling pathway in the HCC model was investigated. 3FC downregulated the constitutive phosphorylation of STAT3 and non-receptor tyrosine kinases such as JAK1 and JAK2. It also suppressed the transportation of STAT3 to the nucleus and reduced its DNA-binding ability. Pervanadate treatment overrode the 3FC-triggered STAT3 inhibition, and the profiling of cellular phosphatase expression revealed an increase in SHP-2 levels upon 3FC treatment. The siRNA-driven deletion of SHP-2 led to reinstate STAT3 activation. 3FC downmodulated the levels of various oncogenic proteins and decreased CXCL12-driven cell migration and invasion. Interestingly, 3FC did not exhibit any substantial toxicity, whereas it significantly regressed tumor growth in an orthotopic HCC mouse model and abrogated lung metastasis. Overall, 3FC can function as a potent agent that can display antitumor activity by targeting STAT3 signaling in HCC models.

scholarly journals Targeting STAT3 in Cancer Immunotherapy

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Sailan Zou ◽  
Qiyu Tong ◽  
Bowen Liu ◽  
Wei Huang ◽  
Yan Tian ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Therapeutic Strategy ◽  
Current Status ◽  
Therapeutic Approaches ◽  
Oncogenic Signaling ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Oncogenic Signaling Pathways ◽  
Transcription 3 ◽  
Cancerous Cells

Abstract As a point of convergence for numerous oncogenic signaling pathways, signal transducer and activator of transcription 3 (STAT3) is central in regulating the anti-tumor immune response. STAT3 is broadly hyperactivated both in cancer and non-cancerous cells within the tumor ecosystem and plays important roles in inhibiting the expression of crucial immune activation regulators and promoting the production of immunosuppressive factors. Therefore, targeting the STAT3 signaling pathway has emerged as a promising therapeutic strategy for numerous cancers. In this review, we outline the importance of STAT3 signaling pathway in tumorigenesis and its immune regulation, and highlight the current status for the development of STAT3-targeting therapeutic approaches. We also summarize and discuss recent advances in STAT3-based combination immunotherapy in detail. These endeavors provide new insights into the translational application of STAT3 in cancer and may contribute to the promotion of more effective treatments toward malignancies.

Mechanism of interaction between TM4SF1 and jak2-stat3 signaling pathway in lung cancer cells and expression analysis in non-small cell lung cancer

2020 ◽  
Author(s):  
Yumeng Niu ◽  
Hailong Deng ◽  
Lipeng Li ◽  
Weikang Chen ◽  
Yuxuan Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Signaling Pathway ◽  
A549 Cells ◽  
Normal Lung ◽  
Expression Levels ◽  
Qrt Pcr ◽  
Stat3 Signaling ◽  
Skin Cancers ◽  
Stat3 Signaling Pathway ◽  
Cancer Tissues

Abstract Background According to the latest data released in 2018, it is estimated that there will be 18.1 million new cancer cases worldwide (excluding 1.7 million non-melanoma skin cancers) and 9.6 million cancer deaths (excluding 950 non-melanoma skin cancers) Million cases). Among them, the incidence of lung cancer (11.6% of the total number of cases) and mortality (18.4% of the total number of cancer deaths, which are expected to cause 1.8 million deaths) are the first. In recent years, studies have found TM4SF1 play an important role in the development process of many tumors.Methods Sixty-one patients with NSCLC who underwent surgical resection of cancer tissues, para-carcinoma tissues, and 10 normal lung tissues removed from benign lung disease (Jun/2018-Dec/2018) were collected. Real-time immunofluorescence quantitative PCR (qRT-PCR) and Western blot were used to detect the expression of TM4SF1 in NSCLC tissues (CT), para-carcinoma tissue (PCT), and normal lung tissues(NLT). TM4SF1 gene was overexpressed in lung cancer A549 cells using lentiviral transfection technology, qRT-PCR and Western blot were used to detect whether TM4SF1 gene was successfully expressed in lung cancer A549 cells, and Transwell was used to detect the effect of TM4SF1 overexpression on A549 migration. JAK2-STAT3 signal pathway interference reagent AG490 was used to analyze the expression levels of Stat3 and downstream Sox2 genes in the overexpression group, blank group, negative control group and their corresponding treatment groups TM4SF1, JAK2-STAT3 signal pathway using real-time qRT-PCR. Analyze the relevance of these three indicators at the same time.Results The expression levels of TM4SF1 mRNA and protein in cancer tissues were significantly higher than those in adjacent cancer tissues (P<0.05) and normal lung tissue specimens (P <0.05). The expression of TM4SF1 was not significantly associated with the age and sex of patients, but was associated with tumor size, degree of differentiation, lymph node metastasis, and clinical stage were related (P<0.05). TM4SF1 was successfully overexpressed in A549 cells. After overexpressing TM4SF1, the ability to migrate of A549 cells was significantly enhanced, and the expression levels of Stat3 and downstream Sox2 in the JAK2-STAT3 signaling pathway were up-regulated. The expression of TM4SF1, Stat3 and Sox2 at the mRNA level showed a positive correlation trend (P<0.01).Conclusion TM4SF1 is highly expressed in NSCLC, and its expression level is closely related to many clinical staging indicators. Overexpression of this gene can promote the migration of A549 cells and up-regulate the expression levels of Stat3 and downstream Sox2 in the JAK2-STAT3 signaling pathway. The expressions of TM4SF1, Stat3 and Sox2 were positively correlated in A549 cells. TM4SF1 may promote the occurrence, development and distant metastasis of NSCLC through this pathway. TM4SF1 may become a potential therapeutic target for NSCLC.

scholarly journals Interplay between microRNAs and the STAT3 signaling pathway in human cancers

2013 ◽  
Vol 45 (24) ◽  
pp. 1206-1214 ◽  
Author(s):  
Qing Cao ◽  
Yun-Yun Li ◽  
Wen-Feng He ◽  
Zhong-Zu Zhang ◽  
Qin Zhou ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Messenger Rna ◽  
Cancer Therapeutics ◽  
Protein Coding ◽  
Reciprocal Regulation ◽  
Regulate Gene Expression ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Egfr Genes ◽  
Transcription 3

MicroRNAs (miRNAs, also miR) are a class of noncoding endogenous RNAs that regulate gene expression through binding to protein-coding messenger RNA (mRNA) molecules, predominantly within the 3′-untranslated region (3′-UTR). Signal transducer and activator of transcription 3 ( STAT3) is a transcription factor that regulates a battery of genes involved in regulating a variety of biological processes. There is a growing body of evidence demonstrating that miRNAs are closely associated with the STAT3 signaling pathway. In this review, we focus on interactions between miRNAs and the STAT3 signaling pathway, focusing on their reciprocal regulation and roles in cancer. For instance, several papers independently support the existence of regulatory feedback loops between miRNAs and the STAT3 pathway in different cancer contexts including IL-6-STAT3-miR-24/miR-629-HNF4α-miR-124 and IL-6R-STAT3-NF-κB-Lin-28-let-7a. Furthermore, several miRNA components are reported to be involved in STAT3-mediated tumorigenesis, for example miR-21, miR-155, and miR-181b. Through binding to STAT3-binding sites within the promoters of these oncomiRs, STAT3 activates their transcription and mediates tumorigenesis. Some miRNAs directly modulate STAT3 activity through targeting the STAT3 3′-UTR; other miRNAs target SOCS, PIAS3, and EGFR genes, which encode proteins that regulate the STAT3 signaling pathway. Given that miRNAs represent a newly discovered class of regulatory molecules, investigating their biological functions and contribution to pathologies caused by STAT3 dysregulation is essential to improve our understanding of tumorigenesis and to develop novel anticancer therapeutics. The more we can learn about miRNAs- STAT3 interactions, the better able we will be to manipulate them for developing cancer therapeutics.

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