scholarly journals Role of the JAK/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6/E7 Oncoproteins

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2297
Author(s):  
Adriana Gutiérrez-Hoya ◽  
Isabel Soto-Cruz
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Critical Role ◽  
Janus Kinase ◽  
Tumor Cell Death ◽  
Cellular Mechanisms ◽  
Poor Overall Survival ◽  
Stat Proteins ◽  
Stat Signaling ◽  
Stat Pathway

The janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is associated with the regulation of essential cellular mechanisms, such as proliferation, invasion, survival, inflammation, and immunity. Aberrant JAK/STAT signaling contributes to cancer progression and metastatic development. STAT proteins play an essential role in the development of cervical cancer, and the inhibition of the JAK/STAT pathway may be essential for enhancing tumor cell death. Persistent activation of different STATs is present in a variety of cancers, including cervical cancer, and their overactivation may be associated with a poor prognosis and poor overall survival. The oncoproteins E6 and E7 play a critical role in the progression of cervical cancer and may mediate the activation of the JAK/STAT pathway. Inhibition of STAT proteins appears to show promise for establishing new targets in cancer treatment. The present review summarizes the knowledge about the participation of the different components of the JAK/STAT pathway and the participation of the human papillomavirus (HPV) associated with the process of cellular malignancy.

scholarly journals The circular RNA circZFR phosphorylates Rb promoting cervical cancer progression by regulating the SSBP1/CDK2/cyclin E1 complex

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Mingyi Zhou ◽  
Zhuo Yang ◽  
Danbo Wang ◽  
Peng Chen ◽  
Yong Zhang
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Circular Rna ◽  
Circular Rnas ◽  
Cyclin E1 ◽  
Normal Tissues ◽  
Exact Function ◽  
Potential Biomarker

Abstract Background As a novel type of non-coding RNA, circular RNAs (circRNAs) play a critical role in the initiation and development of various diseases, including cancer. However, the exact function of circRNAs in human cervical cancer remains largely unknown. Methods We identified the circRNA signature of upregulated circRNAs between cervical cancer and paired adjacent normal tissues. Using two different cohorts and GEO database, a total of six upregulated circRNAs were identified with a fold change > 2, and P < 0.05. Among these six circRNAs, hsa_circ_0072088 (circZFR) was the only exonic circRNA significantly overexpressed in cervical cancer. Functional experiments were performed to investigate the biological function of circZFR. CircRNA pull-down, circRNA immunoprecipitation (circRIP) and Co-immunoprecipitation (Co-IP) assays were executed to investigate the molecular mechanism underlying the function of circZFR. Results Functionally, circZFR knockdown represses the proliferation, invasion, and tumor growth. Furthermore, circRNA pull-down experiments combined with mass spectrometry unveil the interactions of circZFR with Single-Stranded DNA Binding Protein 1 (SSBP1). Mechanistically, circZFR bound with SSBP1, thereby promoting the assembly of CDK2/cyclin E1 complexes. The activation of CDK2/cyclin E1 complexes induced p-Rb phosphorylation, thus releasing activated E2F1 leading to cell cycle progression and cell proliferation. Conclusion Our findings provide the first evidence that circZFR is a novel onco-circRNA and might be a potential biomarker and therapeutic target for cervical cancer patients.

scholarly journals The circular RNA circZFR phosphorylates Rb promoting cervical cancer progression by regulating the SSBP1/CDK2/cyclin E1 complex

2021 ◽  
Author(s):  
Mingyi Zhou ◽  
Zhuo Yang ◽  
Danbo Wang ◽  
Peng Chen ◽  
Yong Zhang
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Circular Rna ◽  
Circular Rnas ◽  
Cyclin E1 ◽  
Normal Tissues ◽  
Exact Function ◽  
Potential Biomarker

Abstract Background: As a novel type of non-coding RNA, circular RNAs (circRNAs) play a critical role in the initiation and development of various diseases, including cancer. However, the exact function of circRNAs in human cervical cancer remains largely unknown. Methods: We identified the circRNA signature of upregulated circRNAs between cervical cancer and paired adjacent normal tissues. Using two different cohorts and GEO database, a total of six upregulated circRNAs were identified with a fold change >2, and P <0.05. Among these six circRNAs, hsa_circ_0072088 (circZFR) was the only exonic circRNA significantly overexpressed in cervical cancer. Functional experiments were performed to investigate the biological function of circZFR. CircRNA pull-down, circRNA immunoprecipitation (circRIP) and Co-immunoprecipitation (Co-IP) assays were executed to investigate the molecular mechanism underlying the function of circZFR.Results: Functionally, circZFR knockdown represses the proliferation, invasion, and tumor growth. Furthermore, circRNA pull-down experiments combined with mass spectrometry unveil the interactions of circZFR with Single-Stranded DNA Binding Protein 1 (SSBP1). Mechanistically, circZFR bound with SSBP1, thereby promoting the assembly of CDK2/cyclin E1 complexes. The activation of CDK2/cyclin E1 complexes induced p-Rb phosphorylation, thus releasing activated E2F1 leading to cell cycle progression and cell proliferation. Conclusion: Our findings provide the first evidence that circZFR is a novel onco-circRNA and might be a potential biomarker and therapeutic target for cervical cancer patients.

scholarly journals The use of Drosophila Melanogaster as a Model Organism to study the effect of Innate Immunity on Metabolism

2020 ◽  
Author(s):  
Abeer Mohbeddin ◽  
Nawar Haj Ahmed ◽  
Layla Kamareddine
Keyword(s):  
Drosophila Melanogaster ◽  
Fat Body ◽  
Model Organism ◽  
Fruit Fly ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Metabolic Homeostasis ◽  
Stat Signaling ◽  
Stat Pathway

Apart from its traditional role in disease control, recent body of evidence has implicated a role of the immune system in regulating metabolic homeostasis. Owing to the importance of this “immune-metabolic alignment” in dictating a state of health or disease, a proper mechanistic understanding of this alignment is crucial in opening up for promising therapeutic approaches against a broad range of chronic, metabolic, and inflammatory disorders like obesity, diabetes, and inflammatory bowel syndrome. In this project, we addressed the role of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) innate immune pathway in regulating different metabolic parameters using the Drosophila melanogaster (DM) fruit fly model organism. Mutant JAK/STAT pathway flies with a systemic knockdown of either Domeless (Dome) [domeG0282], the receptor that activates JAK/STAT signaling, or the signal-transducer and activator of transcription protein at 92E (Stat92E) [stat92EEY10528], were used. The results of the study revealed that blocking JAK/STAT signaling alters the metabolic profile of mutant flies. Both domeG0282 and stat92EEY10528 mutants had an increase in body weight, lipid deprivation from their fat body (lipid storage organ in flies), irregular accumulation of lipid droplets in the gut, systemic elevation of glucose and triglyceride levels, and differential down-regulation in the relative gene expression of different peptide hormones (Tachykinin, Allatostatin C, and Diuretic hormone 31) known to regulate metabolic homeostasis in flies. Because the JAK/STAT pathway is evolutionary conserved between invertebrates and vertebrates, our potential findings in the fruit fly serves as a platform for further immune-metabolic translational studies in more complex mammalian systems including humans.

scholarly journals The circular RNA circZFR phosphorylates Rb promoting cervical cancer progression by regulating the SSBP1/CDK2/cyclin E1 complex

2021 ◽  
Author(s):  
Mingyi Zhou ◽  
Zhuo Yang ◽  
Danbo Wang ◽  
Peng Chen ◽  
Yong Zhang
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
Circular Rna ◽  
Circular Rnas ◽  
Cyclin E1 ◽  
Normal Tissues ◽  
Exact Function ◽  
Potential Biomarker

Abstract Background: As a novel type of non-coding RNA, circular RNAs (circRNAs) play a critical role in the initiation and development of various diseases, including cancer. However, the exact function of circRNAs in human cervical cancer remains largely unknown. Methods: We identified the circRNA signature of upregulated circRNAs between cervical cancer and paired adjacent normal tissues. Using two different cohorts and GEO database, a total of six upregulated circRNAs were identified with a fold change >2, and P <0.05. Among these six circRNAs, hsa_circ_0072088 (circZFR) was the only exonic circRNA significantly overexpressed in cervical cancer. Functional experiments were performed to investigate the biological function of circZFR. CircRNA pull-down, circRNA immunoprecipitation (circRIP) and Co-immunoprecipitation (Co-IP) assays were executed to investigate the molecular mechanism underlying the function of circZFR.Results: Functionally, circZFR knockdown represses the proliferation, invasion, and tumor growth. Furthermore, circRNA pull-down experiments combined with mass spectrometry unveil the interactions of circZFR with Single-Stranded DNA Binding Protein 1 (SSBP1). Mechanistically, circZFR bound with SSBP1, thereby promoting the assembly of CDK2/cyclin E1 complexes. The activation of CDK2/cyclin E1 complexes induced p-Rb phosphorylation, thus releasing activated E2F1 leading to cell cycle progression and cell proliferation. Conclusion: Our findings provide the first evidence that circZFR is a novel onco-circRNA and might be a potential biomarker and therapeutic target for cervical cancer patients.

scholarly journals The Janus kinase inhibitor (baricitinib) suppresses the rheumatoid arthritis active marker gliostatin/thymidine phosphorylase in human fibroblast-like synoviocytes

2022 ◽  
Author(s):  
Yuji Joyo ◽  
Yohei Kawaguchi ◽  
Hiroki Yonezu ◽  
Hiroya Senda ◽  
Sanshiro Yasuma ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Thymidine Phosphorylase ◽  
Kinase Inhibitor ◽  
Cartilage Destruction ◽  
Janus Kinase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Stat Proteins ◽  
Protein Levels ◽  
Stat Signaling ◽  
Fibroblast Like Synoviocytes

AbstractGliostatin/thymidine phosphorylase (GLS/TP) is known to have angiogenic and arthritogenic activities in the pathogenesis of rheumatoid arthritis (RA). The novel oral Janus kinase (JAK) inhibitor baricitinib has demonstrated high efficacy in RA. However, the effect of baricitinib on fibroblast-like synoviocytes (FLSs), a key component of invasive synovitis, has not been still elucidated. This study investigated whether GLS/TP production could be regulated by JAK/signal transducers and activators of transcription (STAT) signaling in FLSs derived from patients with RA. FLSs were cultured and stimulated by interferon (IFN)γ in the presence of baricitinib. Expression levels of GLS/TP were determined using reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunocytochemistry. Phosphorylation of STAT proteins was investigated by Western blot. In cultured FLSs, GLS/TP mRNA and protein levels were significantly induced by treatment with IFNγ and these inductions were suppressed by baricitinib treatment. Baricitinib inhibited IFNγ-induced STAT1 phosphorylation, while JAK/STAT activation played a pivotal role in IFNγ-mediated GLS/TP upregulation in RA. These results suggested that baricitinib suppressed IFNγ-induced GLS/TP expression by inhibiting JAK/STAT signaling, resulting in the attenuation of neovascularization, synovial inflammation, and cartilage destruction.

scholarly journals Balanced JAK/STAT signaling is critical to maintain the functional and structural integrity of the Drosophila respiratory epithelium

2020 ◽  
Author(s):  
Xiao Niu ◽  
Christine Fink ◽  
Kimberley Kallsen ◽  
Viktoria Mincheva ◽  
Sören Franzenburg ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Lung Diseases ◽  
Structural Changes ◽  
Structural Integrity ◽  
Respiratory Epithelium ◽  
Janus Kinase ◽  
Chronic Obstructive ◽  
Chronic Lung Diseases ◽  
Stat Signaling ◽  
Stat Pathway

SummarySignals mediated by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway play a central role in maintaining homeostasis in a multitude of tissues. A large number of studies have shown that this role is particularly prominent in the lungs. Deregulation of the JAK/STAT signaling pathway is causally linked with various, mostly chronic, lung diseases, including lung cancer, asthma, and chronic obstructive pulmonary disease. To elucidate the molecular framework that explains how deregulated JAK/STAT signaling gives rise to pathogenic states, we used the fruit fly Drosophila as a model. While the JAK/STAT pathway is characterized by high structural diversity and complexity in vertebrates, it is relatively simple in Drosophila. The JAK/STAT pathway was active in almost all respiratory epithelial cells of larvae and adult flies. Stressful stimuli, such as cigarette smoke, evoked strong and regionalized activation of the JAK/STAT pathway, which was most likely driven by the concurrently induced ligand Unpaired 2. Inhibition of JAK/STAT signaling induced apoptotic processes in epithelial cells. The aforementioned chronic lung diseases are associated with increased activity of the JAK/STAT pathway and are treated with specific JAK inhibitors. Therefore, we investigated the effects of increased JAK/STAT signaling in the respiratory epithelium of Drosophila. Ectopic activation of the JAK/STAT pathway led to premature death at the larval or pupal stage. Furthermore, it induced major structural changes in epithelial cells, which almost completely lost their typical characteristics. These structural changes led to considerable thickening of the epithelium, substantial narrowing of the air-conducting space, and disruption of the tracheal epicuticular structure. Pharmacological interference of JAK/STAT signaling reverted this phenotype. Activation of the JAK/STAT pathway also affected vesicle-mediated transport, which led to erroneous trafficking of typical junction proteins. In summary, these results demonstrate that balanced JAK/STAT signaling is essential for the normal functionality of the respiratory epithelium and thus the entire organ. A basal level of JAK/STAT signaling is required for cellular processes such as growth and division. However, chronic overactivation of this signaling leads to massive structural changes that are closely related to pathologies typically seen in chronic inflammatory lung diseases.

The association of miR-138 variants with the prognosis of cervical cancer

2020 ◽  
Author(s):  
Shuangqing Cao ◽  
Lei Zheng
Keyword(s):  
Cervical Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Cox Regression ◽  
Critical Role ◽  
Expression Level ◽  
Poor Overall Survival ◽  
Cox Regression Analysis ◽  
Normal Tissues ◽  
Kaplan Meier

Abstract Background MicroRNA-138 (miR-138) is shown to inhibit tumor growth and played a critical role in tumor pathogenesis, the present study aimed to investigate the prognistic value of miR-138 in cervical cancer. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) assay was used to detect the expression of miR-138 in the tissues of cervical cancer and adjacent normal tissues. The association of miR-138 expression with clinical characteristic was analyzed via χ2 test. Then Kaplan-Meier analysis was performed to analyze the association of miR-138 expression with the overall survival of cervical cancer patients. The multivariate cox analysis was used to evaluate the prognostic value of miR-138. Results In the current study, we found the expression level of miR-138 was significantly downregulated in the most cervical cancer patients tissues compared with that in the adjacent normal tissues (P < 0.001). And its expression was closely affected by TNM stage (P = 0.043), lymph node metastasis (P = 0.011) and FIGO stage (P = 0.002). Kaplan-Meier analysis result showed that the decreased expression level of miR-138 expression was associated with poor overall survival of patients. The cox regression analysis result indicated that miR-138 expression was independently associated with the overall survival. Conclusions The expression of miR-138 is down-regulated and involved in the development of cervical cancer. Moreover, it may serve as a prognostic marker for patients with cervical cancer.

scholarly journals Inhibition of vesicular stomatitis virus infection in epithelial cells by alpha interferon-induced soluble secreted proteins

2006 ◽  
Vol 87 (9) ◽  
pp. 2653-2662 ◽  
Author(s):  
Mausumi Basu ◽  
Ratan K. Maitra ◽  
Yan Xiang ◽  
Xiangzhi Meng ◽  
Amiya K. Banerjee ◽  
...  
Keyword(s):  
Vesicular Stomatitis Virus ◽  
Critical Role ◽  
Janus Kinase ◽  
Secreted Proteins ◽  
Alternative Mechanism ◽  
Oligoadenylate Synthetase ◽  
Vesicular Stomatitis ◽  
Antiviral Proteins ◽  
Antiviral Mechanism ◽  
Stat Pathway

Interferons (IFNs) are potent antiviral cytokines that inhibit infection by a wide spectrum of viruses by activating the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. Several IFN-induced antiviral proteins including 2′,5′-oligoadenylate synthetase, dsRNA-activated protein kinase and Mx play a critical role in conferring the antiviral properties of IFN. However, studies have shown that additional antiviral factors are involved in addition to these proteins during IFN-mediated antiviral action. In an effort to characterize these novel antiviral factors, the antiviral mechanism of alpha IFN (IFN-α) against vesicular stomatitis virus (VSV) was investigated in human lung epithelial A549 cells. These studies demonstrated that soluble secreted antiviral proteins as the constituents of conditioned medium prepared from IFN-α-treated cells reduced VSV infectivity by more than 2 logs, compared with a 4 log inhibition observed following treatment of cells with IFN-α. The antiviral mechanism of these secreted proteins appeared to act at the level of cellular entry of VSV. Interestingly, the IFN-α-induced antiviral proteins were secreted independently of STAT1 (an essential component of the JAK/STAT pathway), demonstrating that the release of such extracellular soluble antiviral proteins from cells may represent an alternative mechanism of the antiviral defence strategy of IFN towards VSV infection.

scholarly journals Metastatic suppression by DOC2B is mediated by inhibition of epithelial-mesenchymal transition and induction of senescence

2021 ◽  
Author(s):  
Samatha Bhat ◽  
Divya Adiga ◽  
Vaibhav Shukla ◽  
Kanive Parashiva Guruprasad ◽  
Shama Prasada Kabekkodu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Vesicle Trafficking ◽  
Critical Role ◽  
Anoikis Resistance ◽  
Mesenchymal Transition ◽  
Intracellular Vesicle

AbstractSenescence induction and epithelial-mesenchymal transition (EMT) events are the opposite sides of the spectrum of cancer phenotypes. The key molecules involved in these processes may get influenced or altered by genetic and epigenetic changes during tumor progression. Double C2-like domain beta (DOC2B), an intracellular vesicle trafficking protein of the double C2 protein family, plays a critical role in exocytosis, neurotransmitter release, and intracellular vesicle trafficking. DOC2B is repressed by DNA promoter hypermethylation and functions as a tumor growth regulator in cervical cancer. To date, the molecular mechanisms of DOC2B in cervical cancer progression and metastasis is elusive. Herein, the biological functions and molecular mechanisms regulated by DOC2B and its impact on senescence and EMT are described. DOC2B inhibition promotes proliferation, growth, and migration by relieving G0/G1-S arrest, actin remodeling, and anoikis resistance in Cal27 cells. It enhanced tumor growth and liver metastasis in nude mice with the concomitant increase in metastasis-associated CD55 and CD61 expression. Inhibition of EMT and promotion of senescence by DOC2B is a calcium-dependent process and accompanied by calcium-mediated interaction between DOC2B and CDH1. In addition, we have identified several EMT and senescence regulators as targets of DOC2B. We show that DOC2B may act as a metastatic suppressor by inhibiting EMT through induction of senescence via DOC2B-calcium-EMT-senescence axis. Graphical abstract

scholarly journals The JAK/STAT signaling pathway: from bench to clinic

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Xiaoyi Hu ◽  
Jing li ◽  
Maorong Fu ◽  
Xia Zhao ◽  
Wei Wang
Keyword(s):  
Signaling Pathway ◽  
Current Knowledge ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Quarter Century ◽  
Cellular Processes ◽  
Stat Signaling ◽  
Cancer And Inflammation ◽  
Stat Pathway

AbstractThe Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pathway. Moreover, we highlight the role of the JAK/STAT pathway and its inhibitors in various diseases.

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