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.

scholarly journals O-GlcNAcylation is essential for rapid Pomc expression and cell proliferation in corticotropic tumor cells

2021 ◽  
Author(s):  
Logan J Massman ◽  
Michael Pereckas ◽  
Nathan T Zwagerman ◽  
Stephanie Olivier-Van Stichelen
Keyword(s):  
Pituitary Adenoma ◽  
Cellular Proliferation ◽  
Endocrine Function ◽  
Dependent Manner ◽  
Post Translational Modification ◽  
Cushing Disease ◽  
Human Proteins ◽  
Acth Secreting ◽  
The Impact

Pituitary adenomas have a staggering 16.7% lifetime prevalence and can be devastating in many patients due to profound endocrine and neurologic dysfunction. To date, no clear genomic or epigenomic markers correlates with their onset or severity. Herein, we investigate the impact of the O-GlcNAc post-translational modification in their etiology. Found in over 5000 human proteins to date, O-GlcNAcylation dynamically regulates proteins in critical signaling pathways, and its deregulation is involved in cancers progression and endocrine diseases such as diabetes. In this study, we demonstrate that O-GlcNAcylation enzymes were upregulated, particularly in aggressive 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 show that the endocrine function of pituitary adenoma is also dependent on O-GlcNAcylation. In corticotropic tumors, hyper-secretion of the proopiomelanocortin (POMC)-derived hormone ACTH leads to Cushing disease, materialized by severe endocrine disruption and increased mortality. We demonstrate that Pomc mRNA is stabilized in an O-GlcNAc-dependent manner in response to corticotropic-stimulating hormone (CRH). By impacting 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.

scholarly journals Systemic Platelet-activating Factor Receptor Activation Augments Experimental Lung Tumor Growth and Metastasis

2014 ◽  
Vol 7 ◽  
pp. CGM.S14501 ◽  
Author(s):  
Patrick C. Hackler ◽  
Sarah Reuss ◽  
Raymond L. Konger ◽  
Jeffrey B. Travers ◽  
Ravi P. Sahu
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Lung Tumor ◽  
Platelet Activating Factor ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Melanoma Tumor ◽  
Tumor Growth And Metastasis ◽  
The Impact

Pro-oxidative stressors including cigarette smoke (CS) generate novel lipids with platelet-activated factor-receptor (PAF-R) agonistic activity mediate systemic immunosuppression, one of the most recognized events in promoting carcinogenesis. Our previous studies have established that these oxidized-PAF-R-agonists augment murine B16F10 melanoma tumor growth in a PAF-R-dependent manner because of its effects on host immunity. As CS generates PAF-R agonists, the current studies sought to determine the impact of PAF-R agonists on lung cancer growth and metastasis. Using the murine Lewis Lung Carcinoma (LLC1) model, we demonstrate that treatment of C57BL/6 mice with a PAF-R agonist augments tumor growth and lung metastasis in a PAF-R-dependent manner as these findings were not seen in PAF-R-deficient mice. Importantly, this effect was because of host rather than tumor cells PAF-R dependent as LLC1 cells do not express functional PAF-R. These findings indicate that experimental lung cancer progression can be modulated by the PAF system.

scholarly journals Long-Pentraxin 3 Affects Primary Cilium in Zebrafish Embryo and Cancer Cells via the FGF System

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1756
Author(s):  
Jessica Guerra ◽  
Paola Chiodelli ◽  
Chiara Tobia ◽  
Claudia Gerri ◽  
Marco Presta
Keyword(s):  
Embryonic Development ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Primary Cilium ◽  
Zebrafish Embryo ◽  
Dependent Manner ◽  
Pentraxin 3 ◽  
Left Right Asymmetry ◽  
The Impact ◽  
Cilium Length

Primary cilium drives the left-right asymmetry process during embryonic development. Moreover, its dysregulation contributes to cancer progression by affecting various signaling pathways. The fibroblast growth factor (FGF)/FGF receptor (FGFR) system modulates primary cilium length and plays a pivotal role in embryogenesis and tumor growth. Here, we investigated the impact of the natural FGF trap long-pentraxin 3 (PTX3) on the determination of primary cilium extension in zebrafish embryo and cancer cells. The results demonstrate that down modulation of the PTX3 orthologue ptx3b causes the shortening of primary cilium in zebrafish embryo in a FGF-dependent manner, leading to defects in the left-right asymmetry determination. Conversely, PTX3 upregulation causes the elongation of primary cilium in FGF-dependent cancer cells. Previous observations have identified the PTX3-derived small molecule NSC12 as an orally available FGF trap with anticancer effects on FGF-dependent tumors. In keeping with the non-redundant role of the FGF/FGR system in primary cilium length determination, NSC12 induces the elongation of primary cilium in FGF-dependent tumor cells, thus acting as a ciliogenic anticancer molecule in vitro and in vivo. Together, these findings demonstrate the ability of the natural FGF trap PTX3 to exert a modulatory effect on primary cilium in embryonic development and cancer. Moreover, they set the basis for the design of novel ciliogenic drugs with potential implications for the therapy of FGF-dependent tumors.

scholarly journals The Impact of miRNA in Colorectal Cancer Progression and Its Liver Metastases

2018 ◽  
Vol 19 (12) ◽  
pp. 3711 ◽  
Author(s):  
Ovidiu Balacescu ◽  
Daniel Sur ◽  
Calin Cainap ◽  
Simona Visan ◽  
Daniel Cruceriu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Cancer Progression ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Cancer Management ◽  
Incidence And Mortality ◽  
The Impact

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality rate. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/βcatenin, EGFR, TGFβ and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial–mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner.

Plasma microparticles of sickle patients during crisis or taking hydroxyurea modify endothelium inflammatory properties

Blood ◽  
2020 ◽  
Vol 136 (2) ◽  
pp. 247-256 ◽  
Author(s):  
Yohann Garnier ◽  
Séverine Ferdinand ◽  
Marie Garnier ◽  
Kizzy-Clara Cita ◽  
Régine Hierso ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell ◽  
Messenger Rna ◽  
Ex Vivo ◽  
Biological Effects ◽  
Annexin V ◽  
Neutrophil Adhesion ◽  
Dependent Manner ◽  
High Concentration ◽  
The Impact

Abstract Microparticles (MPs) are submicron extracellular vesicles exposing phosphatidylserine (PS), detected at high concentration in the circulation of sickle cell anemia (SS) patients. Several groups studied the biological effects of MPs generated ex vivo. Here, we analyzed for the first time the impact of circulating MPs on endothelial cells (ECs) from 60 sickle cell disease (SCD) patients. MPs were collected from SCD patients and compared with MPs isolated from healthy individuals (AA). Other plasma MPs were purified from SS patients before and 2 years after the onset of hydroxyurea (HU) treatment or during a vaso-occlusive crisis and at steady-state. Compared with AA MPs, SS MPs increased EC ICAM-1 messenger RNA and protein levels, as well as neutrophil adhesion. We showed that ICAM-1 overexpression was primarily caused by MPs derived from erythrocytes, rather than from platelets, and that it was abolished by MP PS capping using annexin V. MPs from SS patients treated with HU were less efficient to induce a proinflammatory phenotype in ECs compared with MPs collected before therapy. In contrast, MPs released during crisis increased ICAM-1 and neutrophil adhesion levels, in a PS-dependent manner, compared with MPs collected at steady-state. Furthermore, neutrophil adhesion was abolished by a blocking anti–ICAM-1 antibody. Our study provides evidence that MPs play a key role in SCD pathophysiology by triggering a proinflammatory phenotype of ECs. We also uncover a new mode of action for HU and identify potential therapeutics: annexin V and anti–ICAM-1 antibodies.

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 Downregulation of HMGA2 by Small Interfering RNA Affects the Survival, Migration, and Apoptosis of Prostate Cancer Cell Line

2021 ◽  
Author(s):  
Shima Khajouee ◽  
Elham Baghbani ◽  
Ali Mohammadi ◽  
Behzad Mansoori ◽  
Dariush Shanehbandi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Prostate Cancer Cell ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Dependent Manner ◽  
Pc3 Cells ◽  
The Impact

Purpose: To investigate the downregulation of High Mobility Group AT-hook 2 (HMGA2) expression by small interfering RNAs (siRNAs) in PC3 prostate cancer cell line. HMGA2 belongs to the non-histone chromatin-binding protein family that serves as a crucial regulator of gene transcription. The overexpression of this gene is positively correlated with various prostate cancer-related properties. Thus, HMGA2 is an emerging target in prostate cancer treatment. This study aimed to examine the impact of siRNAs targeting HMGA2 on the viability, migration, and apoptosis processes of the PC3 prostate cancer cell line. Methods: siRNA transfection was conducted with a liposome-mediated approach. The mRNA and protein expression levels for HMGA2 are evaluated by qRT-PCR and western blot analysis. The cytotoxic properties of HMGA2-siRNA were measured by MTT assay on PC3 cells. The migration of PC3 cells was measured by implementing a wound-healing assay. Apoptosis measurement was also quantified by TUNEL assay. Results: Transfection with siRNA significantly decreased both mRNA and protein levels of the HMGA2 gene in a dose-dependent manner after 48 hours. Also, we demonstrated that the knockdown of HMGA2 led to a reduction in cell viability, migration ability, and enhanced apoptosis of PC3 cells in vitro. Conclusion: Our findings recommend that the specific siRNA of HMGA2 may efficiently be able to decrease prostate cancer progression. Therefore, it may be a promising adjuvant treatment in prostate cancer.

scholarly journals Cushing Disease Due to Ectopic Pituitary Adenoma.

2019 ◽  
pp. 1-5
Keyword(s):  
Pituitary Adenoma ◽  
Pituitary Adenomas ◽  
Adrenocorticotropic Hormone ◽  
Pituitary Tumors ◽  
Pituitary Stalk ◽  
Cushing Disease ◽  
Ectopic Acth ◽  
Common Cause ◽  
Ectopic Pituitary Adenoma ◽  
Acth Secreting

Abstract Adrenocorticotropic hormone (ACTH) - secreting pituitary adenomas are the most common cause of Cushing disease. A pituitary adenoma is rarely ectopic and suprasellar dependent (ectopic) ACTH -secreting pituitary tumors are extremely rare, with few cases described in the literature. Therefore, this study aimed to report the case of a patient with a diagnosis of Cushing disease because of a suprasellar ACTH-secreting tumor attached to the pituitary stalk, requiring a craniotomy.

scholarly journals Host CYP27A1 expression is essential for ovarian cancer progression

2019 ◽  
Vol 26 (7) ◽  
pp. 659-675 ◽  
Author(s):  
Sisi He ◽  
Liqian Ma ◽  
Amy E Baek ◽  
Anna Vardanyan ◽  
Varsha Vembar ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Cellular Proliferation ◽  
Cell Lineage ◽  
Myeloid Cell ◽  
Progression Free Survival ◽  
High Expression ◽  
Dependent Manner ◽  
Primary Metabolite ◽  
X Receptors

There is an urgent need for more effective strategies to treat ovarian cancer. Elevated cholesterol levels are associated with a decreased progression-free survival time (PFS) while statins are protective. 27-Hydroxycholesterol (27HC), a primary metabolite of cholesterol, has been shown to modulate the activities of the estrogen receptors (ERs) and liver x receptors (LXRs) providing a potential mechanistic link between cholesterol and ovarian cancer progression. We found that high expression of CYP27A1, the enzyme responsible for the synthesis of 27HC, was associated with decreased PFS, while high expression of CYP7B1, responsible for 27HC catabolism, was associated with increased PFS. However, 27HC decreased the cellular proliferation of various ovarian cancer cell lines in an LXR-dependent manner. Intriguingly, ID8 grafts were unable to effectively establish in CYP27A1−/− mice, indicating involvement of the host environment. Tumors from mice treated with 27HC had altered myeloid cell composition, and cells from the marrow stem cell lineage were found to be responsible for the effects in CYP27A1−/− mice. While inhibition of CYP27A1 or immune checkpoint did not significantly alter tumor size, their combination did, thereby highlighting this axis as a therapeutic target.

scholarly journals Conditional knockdown of integrin beta-3 reveals its involvement in osteolytic and soft tissue lesions of breast cancer skeletal metastasis

2020 ◽  
Author(s):  
Marineta Kovacheva ◽  
Michael Zepp ◽  
Stefan Berger ◽  
Martin R. Berger
Keyword(s):  
Breast Cancer ◽  
Soft Tissue ◽  
Cancer Progression ◽  
Cellular Proliferation ◽  
Skeletal Metastasis ◽  
Cellular Migration ◽  
Skeletal Metastases ◽  
The Impact

Abstract Integrin β3 (ITGB3) is probably related to skeletal metastasis, which is the most frequent complication in breast cancer progression. We aimed to define its role and suitability as target for anti-metastatic therapy. We generated two MDA-MB-231 cell clones with conditional miRNA-mediated ITGB3 knockdown for analyzing the resulting effects in vitro regarding mRNA expression, proliferation and migration, as well the impact on skeletal metastasis in a nude rat model. Furthermore, ITGB3 levels were analyzed in exosomes from plasma of rats with skeletal metastases, and from MDA-MB-231 cells incubated with these vesicles, as well as from exosomes secreted by cells with conditional ITGB3 knockdown. This inhibition of ITGB3 expression decreased cellular proliferation and more distinctly inhibited cellular migration. Reduction and even complete remissions of respective soft tissue and osteolytic lesions were detected after ITGB3 knockdown in vivo. Furthermore, ITGB3 levels were increased in exosomes isolated from plasma of rats harboring MDA-MB-231 lesions as well as in respective cells incubated with these vesicles in vitro. ITGB3 was distinctly decreased in exosomes from cells with ITGB3 knockdown. The observed in vitro and in vivo anti-ITGB3 effects can be explained by downregulation of specific genes, which have roles in angiogenesis (NPTN, RRM2), tumor growth (NPTN), energy metabolism (ISCA1), cytokinesis (SEPT11), migration (RRM2, STX6), cell proliferation, invasiveness, senescence, tumorigenesis (RRM2) and vesicle trafficking (SEPT11, STX6). ITGB3 has a role in breast cancer skeletal metastasis via gene expression modulation, as mirrored for ITGB3 in exosomes, thus it could serve as target for anti-metastatic therapy.

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