scholarly journals IRF-1 Inhibits Angiogenic Activity of HPV16 E6 Oncoprotein in Cervical Cancer

2020 ◽  
Vol 21 (20) ◽  
pp. 7622
Author(s):  
Seung Bae Rho ◽  
Seung-Hoon Lee ◽  
Hyun-Jung Byun ◽  
Boh-Ram Kim ◽  
Chang Hoon Lee
Keyword(s):  
Cervical Cancer ◽  
Cell Growth ◽  
Cancer Progression ◽  
Cellular Proliferation ◽  
Endothelial Cell Migration ◽  
Dependent Manner ◽  
P53 Expression ◽  
Angiogenic Activity ◽  
Hpv16 E6 ◽  
E6 Oncoprotein

HPV16 E6 oncoprotein is a member of the human papillomavirus (HPV) family that contributes to enhanced cellular proliferation and risk of cervical cancer progression via viral infection. In this study, interferon regulatory factor-1 (IRF-1) regulates cell growth inhibition and transcription factors in immune response, and acts as an HPV16 E6-binding cellular molecule. Over-expression of HPV16 E6 elevated cell growth by attenuating IRF-1-induced apoptosis and repressing p21 and p53 expression, but activating cyclin D1 and nuclear factor kappa B (NF-κB) expression. The promoter activities of p21 and p53 were suppressed, whereas NF-κB activities were increased by HPV16 E6. Additionally, the cell viability of HPV16 E6 was diminished by IRF-1 in a dose-dependent manner. We found that HPV16 E6 activated vascular endothelial growth factor (VEGF)-induced endothelial cell migration and proliferation as well as phosphorylation of VEGFR-2 via direct interaction in vitro. HPV16 E6 exhibited potent pro-angiogenic activity and clearly enhanced the levels of hypoxia-inducible factor-1α (HIF-1α). By contrast, the loss of function of HPV16 E6 by siRNA-mediated knockdown inhibited the cellular events. These data provide direct evidence that HPV16 E6 facilitates tumour growth and angiogenesis. HPV16 E6 also activates the PI3K/mTOR signalling cascades, and IRF-1 suppresses HPV16 E6-induced tumourigenesis and angiogenesis. Collectively, these findings suggest a biological mechanism underlying the HPV16 E6-related activity in cervical tumourigenesis.

scholarly journals HPV16 E6 oncoprotein‐induced upregulation of lncRNA GABPB1‐AS1 facilitates cervical cancer progression by regulating miR‐519e‐5p/Notch2 axis

2020 ◽  
Vol 34 (10) ◽  
pp. 13211-13223
Author(s):  
Rongying Ou ◽  
Mingfen Lv ◽  
Xuan Liu ◽  
Jiangmin Lv ◽  
Jinduo Zhao ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Hpv16 E6 ◽  
E6 Oncoprotein

scholarly journals Novel Role of IMPA2 in AIFM2-Mediated Apoptosis of Cervical Cancer by Targeting p53

2021 ◽  
Author(s):  
Lei Liu ◽  
Min Wang ◽  
Xianping Li ◽  
Bingqi Wang ◽  
Sheng Yin
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Cell Apoptosis ◽  
Immunohistochemical Staining ◽  
Locally Advanced ◽  
Mechanistic Study ◽  
Fluorescence Signal ◽  
Dependent Manner ◽  
P53 Expression ◽  
Novel Therapeutic

Abstract Background Cervical cancer continues to be concerned and the prognosis of locally advanced cervical cancer remains poor, which underscores pivotal needs to find novel therapeutic targets. Previously, we firstly identified Myo-inositol monophosphatase 2(IMPA2) as a potential oncogene and verified its tumor-promoting role in vitro and in vivo. In this study, we further aimed to elucidate the underlying mechanisms of IMPA2 in regulation of tumor apoptosis. Methods Cell apoptosis was assessed by apoptosis-related proteins detecting, flow cytometry, immunofluorescence and immunohistochemical staining. Fluorescence microscope was used to analyze fluorescence signal. The string database was used to find molecules regulated by IMPA2. The expression of apoptosis inducing factor mitochondria associated 2(AIFM2) was determined by qRT-PCR, western blot, immunohistochemical staining and immunofluorescence analysis. Function changes of mitochondria were evaluated by measurements of mitochondrial membrane potential and intracellular Ca2+ levels. CCK-8 assay was used to detected cell viability. Results Apoptosis of cervical cancer cells was markedly promoted when silencing IMPA2. AIFM2 was significantly up-regulated both in mRNA and protein levels, and inhibition of AIFM2 could reserve IMPA2 knockdown-induced apoptosis in a mitochondrial dependent manner. But the analysis of database and our experimental results showed that AIFM2 had little effect on cervical cancer progression and survival. Further mechanistic study revealed that IMPA2 and AIFM2 silencing apparently activated p53 and treatment of p53 inhibitor (Pifithrin α) could rescue IMPA2 knockdown-induced cell apoptosis. Conclusion Our findings displayed a novel function of IMPA2 in regulating cell apoptosis mediated by a disturbance of AIFM2 and p53 expression, potentially making it a novel therapeutic target for cervical cancer treatment.

scholarly journals Hesperidin Induces Mitochondria Mediated Intrinsic Apoptosis in HPV-positive Cervical Cancer Cells via Regulation of E6/p53 Expression

2020 ◽  
Author(s):  
Fang Ren ◽  
Gong Zhang ◽  
Caiyu Li ◽  
Gailing Li ◽  
Yuan Cao ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Protein Level ◽  
Potential Candidate ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
P53 Expression ◽  
Cervical Cancer Cells ◽  
Apoptotic Proteins

Abstract Background: Hesperetin, an active compound found in citrus fruits, possesses antiproliferative effects toward several types of cancer cell lines, including cervical cancer. In this study, we explore the antitumor effects of Hesperetin on the human cervical cancer human papilloma virus (HPV)-positive (CaSki and HeLa) and HPV-negative (C-33A) cell lines and further elucidated the underlying mechanisms of this action. Methods: Cell viability and proliferation was measured by the MTT assay and 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay, respectively. dUTP-fluorescein nick end-labeling (TUNEL) staining, Annexin V‑fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining and flow cytometry was used to assess the degree of apoptosis. JC-1 staining assay was used to evaluate the change of mitochondrial membrane potential (ΔΨm) and Western blot assays were used to determine apoptosis-related factors at protein level. Results: Hesperetin (100, 200 and 400 μM) exhibited a significant exclusive inhibitory effect against the growth of HPV-infected CaSki and HeLa cancer cells via induction of apoptosis in a concentration-dependent manner, while it was almost not active in HPV-negative C-33A cancer cells and normal cervix epithelial H8 cells. Moreover, this antitumor effect executed by Hesperetin was associated with disruption of ΔΨm, the release of cytochrome c from mitochondria, activation of pro-apoptotic proteins (Bax, cleaved caspase-3 and caspase-9) and inhibition of anti-apoptotic proteins (Bcl-2). During this process, cleaved caspase-8 remained unchanged. In addition, Hesperetin led to a downregulation of E6 oncoprotein expression and upregulation of tumor suppressor protein p53 level. Conclusions: Collectively, these results implicated that Hesperetin can induce apoptosis of HPV‑positive cervical cancer cells via a mitochondria-mediated intrinsic signaling pathway, together with the repression of E6 and enhancement of p53 protein level, indicating Hesperetin may be considered as a potential candidate for the development of innovative anti-HPV cervical cancer agents.

scholarly journals LncRNA GHET1 promotes cervical cancer progression through regulating AKT/mTOR and Wnt/β-catenin signaling pathways

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Zhihui Liu ◽  
Sukun Luo ◽  
Meiqin Wu ◽  
Chong Huang ◽  
Huifen Shi ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Growth ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Gynecological Cancer ◽  
Preliminary Investigation ◽  
Loss Of Function ◽  
Down Regulation ◽  
Mesenchymal Transition ◽  
Dismal Prognosis

Abstract Cervical cancer (CC) is a prevalent gynecological cancer, and the patients with CC usually suffer from dismal prognosis. Long non-coding RNAs (lncRNAs) are demonstrated to serve as promising biological targets in human cancers. Gastric carcinoma proliferation enhancing transcript 1 (GHET1) has been revealed to function as an oncogene in several cancers, but it has never been investigated in CC. We proposed to examine the biological role of GHET1 in CC and the underlying mechanism and validated the up-regulated expression of GHET1 in CC cell lines. Loss-of-function assays demonstrated that down-regulation of GHET1 inhibited cell growth, migration and epithelial-to-mesenchymal transition (EMT) in CC. Furthermore, we validated that GHET1 down-regulation could inactivate AKT/mTOR and Wnt/β-catenin pathways, and that respective activation of these two pathways abrogated the inhibitive effect of GHET1 knockdown on CC cell growth, migration and EMT. Moreover, we unfolded a preliminary investigation on the modulation of GHET1 on AKT/mTOR and Wnt/β-catenin pathways. We found that GHET1 stabilized E2F6 mRNA through interacting with IGF2BP2, so as to regulate the activity of AKT/mTOR and Wnt/β-catenin pathways. Rescue assays also proved that GHET1 regulated these two pathways and CC cell growth, migration and EMT through E2F6. In conclusion, we revealed that down-regulation of GHET1 suppresses cervical cancer progression through regulating AKT/mTOR and Wnt/β-catenin signaling pathways, indicating GHET1 as a promising molecular biomarker for CC treatment improvement.

scholarly journals Screening and Identification of Potential iNOS Inhibitors to Curtail Cervical Cancer Progression: An in-Silico Drug Repurposing Approach

2021 ◽  
Author(s):  
PAVAN KUMAR POLEBOYINA ◽  
SMITA C PAWAR ◽  
AKBAR PASHA ◽  
RAVINDER DONETI ◽  
SNEHA MALLESWARI POLEBOYINA ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Tumor Biology ◽  
Drug Repurposing ◽  
Reproductive Age ◽  
Endothelial Cell Migration ◽  
Bonding Energy ◽  
Molegro Virtual Docker ◽  
Drug Candidates ◽  
Inos Inhibitors

Abstract Cervical cancer is the second most common cause of cancer deaths in women worldwide and remains the main reason of mortality amongst women of reproductive age in developing countries. Nitric oxide is involved in several physiological functions inclusive of inflammatory and immune responses. However, the function of NO in tumor biology is debatable. The inducibleNOS (iNOS/NOS2) isoform is the oneresponsible to maintain the levels of NO and it exhibits pleotropic effects in various cancer with concentration-dependent pro- and anti-tumor effects.NOS2 triggers angiogenesis and endothelial cell migration in tumors by regulating the levels of vascular endothelial growth factor (VEGF). In drug discovery, drug repurposing involves investigations of approved drug candidates to treat various other diseases. In this study, we used FDA-approved anti-cancer drugs and small molecules to target iNOS and identify a potential selective iNOS inhibitor. The structures of ligands were geometrically optimized, and energy minimized using Hyperchem software. Molecular docking was performed using Molegro virtual docker and ligands were selected based on MolDock score,Rerank score, and H-bonding energy. In the study showed 4 compounds, Degarelix, Goserelin, Triptorelin pamoate, and venetoclax demonstrated excellent binding affinity to NOS2 protein. These compounds exhibited the lowest MolDock score, Rerank score, with better H-bonding energy to NOS2. Based on the results theses ligands project to be promising potential NOS2 inhibitors to curtail cervical cancer progression

scholarly journals O-GlcNAcylation Is Essential for Rapid Pomc Expression and Cell Proliferation in Corticotropic Tumor Cells

Endocrinology ◽  
2021 ◽  
Vol 162 (12) ◽  
Author(s):  
Logan J Massman ◽  
Michael Pereckas ◽  
Nathan T Zwagerman ◽  
Stephanie Olivier-Van Stichelen
Keyword(s):  
Pituitary Adenoma ◽  
Cancer Progression ◽  
Messenger Rna ◽  
Cellular Proliferation ◽  
Endocrine Function ◽  
Dependent Manner ◽  
Cushing Disease ◽  
Human Proteins ◽  
Acth Secreting ◽  
The Impact

Abstract Pituitary adenomas have a staggering 16.7% lifetime prevalence and can be devastating in many patients because of profound endocrine and neurologic dysfunction. To date, no clear genomic or epigenomic markers correlate with their onset or severity. Herein, we investigate the impact of the O-GlcNAc posttranslational modification in their etiology. Found in more than 7000 human proteins to date, O-GlcNAcylation dynamically regulates proteins in critical signaling pathways, and its deregulation is involved in cancer progression and endocrine diseases such as diabetes. In this study, we demonstrated that O-GlcNAc enzymes were upregulated, particularly in aggressive adrenocorticotropin (ACTH)-secreting tumors, suggesting a role for O-GlcNAcylation in pituitary adenoma etiology. In addition to the demonstration that O-GlcNAcylation was essential for their proliferation, we showed that the endocrine function of pituitary adenoma is also dependent on O-GlcNAcylation. In corticotropic tumors, hypersecretion of the proopiomelanocortin (POMC)-derived hormone ACTH leads to Cushing disease, materialized by severe endocrine disruption and increased mortality. We demonstrated that Pomc messenger RNA is stabilized in an O-GlcNAc-dependent manner in response to corticotrophin-releasing hormone (CRH). By affecting Pomc mRNA splicing and stability, O-GlcNAcylation contributes to this new mechanism of fast hormonal response in corticotropes. Thus, this study stresses the essential role of O-GlcNAcylation in ACTH-secreting adenomas’ pathophysiology, including cellular proliferation and hypersecretion.

Advanced Glycation End Products (AGEs)-Mediated Cell Growth of Human Acute Myelogenous Leukemia Via Mitogen-Activated Protein (MAP) Kinase Pathways.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2762-2762
Author(s):  
Ju Young Kim ◽  
Hyun Ki Park ◽  
Jin Sun Yoon ◽  
Eun Shil Kim ◽  
Kwang Sung Ahn ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cell Lines ◽  
Cellular Proliferation ◽  
Myelogenous Leukemia ◽  
Dependent Manner ◽  
Glycation End Products ◽  
Mitogen Activated Protein ◽  
Acute Myelogenous ◽  
Dose Dependent

Abstract Advanced glycation end products (AGEs) are products of non-enzymatic glycation/oxidation of proteins/lipids that accumulate slowly during natural aging and at a much accelerated rate in a variety of disorders such as diabetes, renal failure, and Alzheimer’s disease. AGE modifications do not only change the physicochemical properties of the afflicted molecules, but also induce cellular signaling, activation of transcription factors and subsequent gene expression in vitro and in vivo. Most of the biologic activities associated with AGEs have been transduced by receptor for AGE (RAGE). Recently, AGEs are known to be in association with diverse cancers in terms of cellular proliferation and metastasis. However, little is known about the role of AGEs in acute myelogenous leukemia (AML). Here we examined the effects of the AGEs-RAGE interaction on the cell proliferation and intracellular signaling of AGEs in human leukemia cell lines. Expression of RAGE was observed in 8 AML cell lines examined, and up-regulated by treatment of AGE. AGE induced the proliferation of AML cell lines, HL60 and HEL, in a dose-dependent manner. Treatment with 5 μM of antisense S-ODN for RAGE did effectively inhibit cell growth of HEL cells. Exposure of HL60 and HEL with AGE induced a significant increase in the numbers of cells in S phase of cell cycle in a dose-dependent manner. AGE enhanced the expression of cell cycle regulatory proteins such as cyclin-dependent kinase (CDK) 2/4/6, cyclin D1/E/B in a dose- and a time-dependent manner. In addition, the protein levels of the cyclin-dependent kinase inhibitor (CDKI), p21 and p27, were decreased by 24 hr exposure of AGE from 10 to 200 μg/ml in HEL. Furthermore, treatment of HEL with 200 μg/ml of AGE triggered activation of mitogen-activated protein (MAP) kinases, Erk, Akt, and p38, pathways and in nuclear translocation of transcription factors NF-kB. These results indicated that AGE induced the cell growth of human AML cells, HL60 and HEL, via augmentation of cell cycle and activation of MAPK kinase pathways. Up-regulation of RAGE by exposure of AGE suggested that cellular proliferation of AML cells might be mediated in autocrine fashion.

scholarly journals The Human Papillomavirus (HPV) E6 Oncoprotein Regulates CD40 Expression via the AT-Hook Transcription Factor AKNA

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 521 ◽  
Author(s):  
Joaquin Manzo-Merino ◽  
Alfredo Lagunas-Martínez ◽  
Carla Contreras-Ochoa ◽  
Marcela Lizano ◽  
Leonardo Castro-Muñoz ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
High Risk ◽  
Immune Surveillance ◽  
Dependent Manner ◽  
Hpv E6 ◽  
E6 Oncoprotein ◽  
Inflammatory State ◽  
Cervical Cancer Development ◽  
Carcinogenic Process

Persistent infection with high-risk Human Papillomavirus (HR-HPV) is the main requisite for cervical cancer development. Normally, HPV is limited to the site of infection and regulates a plethora of cellular elements to avoid the immune surveillance by inducing an anti-inflammatory state, allowing the progress through the viral cycle and the carcinogenic process. Recent findings suggest that the AT-hook transcriptional factor AKNA could play a role in the development of cervical cancer. AKNA is strongly related to the expression of co-stimulatory molecules such CD40/CD40L to achieve an anti-tumoral immune response. To date, there is no evidence demonstrating the effect of the HPV E6 oncoprotein on the AT-hook factor AKNA. In this work, minimal expression of AKNA in cervical carcinoma compared to normal tissue was found. We show the ability of E6 from high-risk HPVs 16 and 18 to interact with and down-regulate AKNA as well as its co-stimulatory molecule CD40 in a proteasome dependent manner. We also found that p53 interacts with AKNA and promotes AKNA expression. Our results indicate that the de-regulation of CD40 and AKNA is induced by the HPV E6 oncoprotein, and this event involves the action of p53 suggesting that the axis E6/p53A/AKNA might play an important role in the de-regulation of the immune system during the carcinogenic process induced by HR-HPV.

Anti-cancer effect of adenovirus p53 on human cervical cancer cell growth in vitro and in vivo

2004 ◽  
Vol 14 (2) ◽  
pp. 322-332 ◽  
Author(s):  
W. S. Ahn ◽  
S. M. Bae ◽  
J. M. Lee ◽  
S. E. Namkoong ◽  
J. Y. Yoo ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Cancer Cell ◽  
Cervical Cancer Cell ◽  
Transduction Efficiency ◽  
Cell Growth Inhibition ◽  
P53 Expression

To evaluate anti-tumor effects of recombinant adenovirus p53, time-course p53, E6 expression, and cell growth inhibition were investigated in vitro and in vivo using cervical cancer cell lines such as CaSki, SiHa, HeLa, HeLaS3, C33A, and HT3. The cell growth inhibition was studied via cell count assay, MTT assay and neutral red assay. After transfecting AdCMVp53 into SiHa cells-xenografted nude mice, the transduction efficiency and anti-tumor effect were investigated for a month. The results showed that adenoviral p53 expression induced significant growth suppression on the cancer cells, in which E6 transcript was strongly repressed, and that the expression of p53 and E6 were remarkably dependent on each cell type. The transduction efficiency was highly maintained in vivo as well as in vitro, and the size of tumor was remarkably decreased in comparison with AdCMVLacZ control. The results suggest that the adenovirus-mediated p53 gene transfection was done very effectively in vitro and in vivo experiment, and the cell growth was suppressed via p53-dependent apoptotic cell death, and that the anti-tumor effect could be related to E6 and p53 expression pattern.

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