scholarly journals Proteome Analysis of USP7 Substrates Revealed Its Role in Melanoma Through PI3K/Akt/FOXO and AMPK Pathways

2021 ◽  
Vol 11 ◽  
Author(s):  
Lanyang Gao ◽  
Danli Zhu ◽  
Qin Wang ◽  
Zheng Bao ◽  
Shigang Yin ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Proteome Analysis ◽  
Human Melanoma ◽  
Ampk Signaling ◽  
Peroxisomal Biogenesis ◽  
C Subunit ◽  
Protein Phosphatase 2

The ubiquitin-specific protease 7 (USP7), as a deubiquitinating enzyme, plays an important role in tumor progression by various mechanisms and serves as a potential therapeutic target. However, the functional role of USP7 in melanoma remains elusive. Here, we found that USP7 is overexpressed in human melanoma by tissue microarray. We performed TMT-based quantitative proteomic analysis to evaluate the A375 human melanoma cells treated with siRNA of USP7. Our data revealed specific proteins as well as multiple pathways and processes that are impacted by USP7. We found that the phosphatidylinositol-3-kinases/Akt (PI3K-Akt), forkhead box O (FOXO), and AMP-activated protein kinase (AMPK) signaling pathways may be closely related to USP7 expression in melanoma. Moreover, knockdown of USP7 in A375 cells, particularly USP7 knockout using CRISPR-Cas9, verified that USP7 regulates cell proliferation in vivo and in vitro. The results showed that inhibition of USP7 increases expression of the AMPK beta (PRKAB1), caspase 7(CASP7), and protein phosphatase 2 subunit B R3 isoform (PPP2R3A), while attenuating expression of C subunit of vacuolar ATPase (ATP6V0C), and peroxisomal biogenesis factor 11 beta (PEX11B). In summary, these findings reveal an important role of USP7 in regulating melanoma progression via PI3K/Akt/FOXO and AMPK signaling pathways and implicate USP7 as an attractive anticancer target for melanoma.

scholarly journals Role of long non-coding RNA TP73-AS1 in cancer

2019 ◽  
Vol 39 (10) ◽  
Author(s):  
Caizhi Chen ◽  
Long Shu ◽  
Wen Zou
Keyword(s):  
Cell Carcinoma ◽  
Signaling Pathways ◽  
Cell Renal Cell Carcinoma ◽  
Aberrant Expression ◽  
Diagnosis And Prognosis ◽  
Early Diagnosis Of Cancer ◽  
Cause Of Deaths

Abstract Cancer incidence rate has increased so much that it is the second leading cause of deaths worldwide after cardiovascular diseases. Sensitive and specific biomarkers are needed for an early diagnosis of cancer and in-time treatment. Recent studies have found that long non-coding RNAs (lncRNAs) participate in cancer tumorigenesis. LncRNA P73 antisense RNA 1T (TP73-AS1), also known as KIAA0495 and p53-dependent apoptosis modulator (PDAM), is located in human chromosomal band 1p36.32 and plays a crucial role in many different carcinomas. This review summarizes current findings on the role of TP73-AS1 and its signaling pathways in various cancers, including glioma, esophageal squamous cell carcinoma (ESCC), hepatocellular carcinoma (HCC), colorectal cancer (CRC), osteosarcoma, gastric cancer (GC), clear cell renal cell carcinoma (ccRCC), breast cancer (BC), bladder cancer, ovarian cancer, cholangiocarcinoma (CCA), lung cancer, and pancreatic cancer. Its aberrant expression generally correlates with clinicopathological characterization of patients. Moreover, TP73-AS1 regulates proliferation, migration, invasion, apoptosis, and chemoresistance cancer mechanisms, both in vivo and in vitro, through different signaling pathways. Therefore, TP73-AS1 may be considered as a marker for diagnosis and prognosis, also as a target for cancer treatment.

scholarly journals p32 promotes melanoma progression and metastasis by targeting EMT markers, Akt/PKB pathway, and tumor microenvironment

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Sunita Sinha ◽  
Satyendra Kumar Singh ◽  
Nitish Jangde ◽  
Rashmi Ray ◽  
Vivek Rai
Keyword(s):  
Tumor Microenvironment ◽  
Human Melanoma ◽  
Migration And Invasion ◽  
Therapy Failure ◽  
Melanoma Tumor ◽  
Melanoma Progression ◽  
Emt Markers

AbstractMelanoma originates from melanin-producing cells called melanocytes. Melanoma poses a great risk because of its rapid ability to spread and invade new organs. Cellular metastasis involves alteration in the gene expression profile and their transformation from epithelial to mesenchymal state. Despite of several advances, metastatic melanoma being a key cause of therapy failure and mortality remains poorly understood. p32 has been found to be involved in various physiological and pathophysiological conditions. However, the role of p32 in melanoma progression and metastasis remains underexplored. Here, we identify the role of p32 in the malignancy of both murine and human melanoma. p32 knockdown leads to reduced cell proliferation, migration, and invasion in murine and human melanoma cells. Furthermore, p32 promotes in vitro tumorigenesis, inducing oncogenes and EMT markers. Mechanistically, we show p32 regulates tumorigenic and metastatic properties through the Akt/PKB signaling pathway in both murine and human melanoma. Furthermore, p32 silencing attenuates melanoma tumor progression and lung metastasis in vivo, modulating the tumor microenvironment by inhibiting the angiogenesis, infiltration of macrophages, and leukocytes in mice. Taken together, our findings identify that p32 drives melanoma progression, metastasis, and regulates the tumor microenvironment. p32 can be a target of a novel therapeutic approach in the regulation of melanoma progression and metastasis.

scholarly journals IL-13 promotes in vivo neonatal cardiomyocyte cell cycle activity and heart regeneration

2019 ◽  
Vol 316 (1) ◽  
pp. H24-H34 ◽  
Author(s):  
Dylan J. Wodsedalek ◽  
Samantha J. Paddock ◽  
Tina C. Wan ◽  
John A. Auchampach ◽  
Aria Kenarsary ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signaling Pathways ◽  
Rna Sequencing ◽  
Akt Signaling ◽  
Heart Regeneration ◽  
Newborn Mice ◽  
Neonatal Cardiomyocyte

There is great interest in identifying signaling mechanisms by which cardiomyocytes (CMs) can enter the cell cycle and promote endogenous cardiac repair. We have previously demonstrated that IL-13 stimulated cell cycle activity of neonatal CMs in vitro. However, the signaling events that occur downstream of IL-13 in CMs and the role of IL-13 in CM proliferation and regeneration in vivo have not been explored. Here, we tested the role of IL-13 in promoting neonatal CM cell cycle activity and heart regeneration in vivo and investigated the signaling pathway(s) downstream of IL-13 specifically in CMs. Compared with control, CMs from neonatal IL-13 knockout (IL-13−/−) mice showed decreased proliferative markers and coincident upregulation of the hypertrophic marker brain natriuretic peptide ( Nppb) and increased CM nuclear size. After apical resection in anesthetized newborn mice, heart regeneration was significantly impaired in IL-13−/− mice compared with wild-type mice. Administration of recombinant IL-13 reversed these phenotypes by increasing CM proliferation markers and decreasing Nppb expression. RNA sequencing on primary neonatal CMs treated with IL-13 revealed activation of gene networks regulated by ERK1/2 and Akt. Western blot confirmed strong phosphorylation of ERK1/2 and Akt in both neonatal and adult cultured CMs in response to IL-13. Our data demonstrated a role for endogenous IL-13 in neonatal CM cell cycle and heart regeneration. ERK1/2 and Akt signaling are important pathways known to promote CM proliferation and protect against apoptosis, respectively; thus, targeting IL-13 transmembrane receptor signaling or administering recombinant IL-13 may be therapeutic approaches for activating proregenerative and survival pathways in the heart. NEW & NOTEWORTHY Here, we demonstrate, for the first time, that IL-13 is involved in neonatal cardiomyocyte cell cycle activity and heart regeneration in vivo. Prior work has shown that IL-13 promotes cardiomyocyte cell cycle activity in vitro; however, the signaling pathways were unknown. We used RNA sequencing to identify the signaling pathways activated downstream of IL-13 in cardiomyocytes and found that ERK1/2 and Akt signaling was activated in response to IL-13.

Stress is a critical player in CYP3A, CYP2C, and CYP2D regulation: role of adrenergic receptor signaling pathways

2012 ◽  
Vol 303 (1) ◽  
pp. E40-E54 ◽  
Author(s):  
Evangelos P. Daskalopoulos ◽  
Foteini Malliou ◽  
Georgia Rentesi ◽  
Marios Marselos ◽  
Matti A. Lang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Adrenergic Receptor ◽  
Drug Efficacy ◽  
Stress System ◽  
Wide Range ◽  
Repeated Restraint Stress ◽  
Pharmacological Manipulations

Stress is a critical player in the regulation of the major cytochrome P-450s ( CYPs) that metabolize the majority of the prescribed drugs. Early in life, maternal deprivation (MD) stress and repeated restraint stress (RS) modified CYP expression in a stress-specific manner. In particular, the expression of CYP3A1 and CYP2C11 was increased in the liver of MD rats, whereas RS had no significant effect. In contrast, hepatic CYP2D1/2 activity was increased by RS, whereas MD did not affect it. The primary effectors of the stress system, glucocorticoids and epinephrine, highly induced CYP3A1/2. Epinephrine also induced the expression of CYP2C11 and CYP2D1/2. Further investigation indicated that AR-agonists may modify CYP regulation. In vitro experiments using primary hepatocyte cultures treated with the AR-agonists phenylephrine, dexmedetomidine, and isoprenaline indicated an AR-induced upregulating effect on the above-mentioned CYPs mediated by the cAMP/protein kinase A and c-Jun NH2-terminal kinase signaling pathways. Interestingly though, in vivo pharmacological manipulations of ARs using the same AR-agonists led to a suppressed hepatic CYP expression profile, indicating that the effect of the complex network of central and peripheral AR-linked pathways overrides that of the hepatic ARs. The AR-mediated alterations in CYP3A1/2, CYP2C11, and CYP2D1/2 expressions are potentially connected with those observed in the activation of signal transducer and activator of transcription 5b. In conclusion, stress and AR-agonists may modify the expression of the major CYP genes involved in the metabolism of drugs used in a wide range of diseases, thus affecting drug efficacy and toxicity.

scholarly journals The Role of Small Molecules and Their Effect on the Molecular Mechanisms of Early Retinal Organoid Development

2021 ◽  
Vol 22 (13) ◽  
pp. 7081
Author(s):  
Philip E. Wagstaff ◽  
Andrea Heredero Berzal ◽  
Camiel J. F. Boon ◽  
Peter M. J. Quinn ◽  
Anneloor L. M. A. ten Asbroek ◽  
...  
Keyword(s):  
Small Molecules ◽  
Signaling Pathways ◽  
Hedgehog Signaling ◽  
Molecular Mechanisms ◽  
Retinal Development ◽  
Comprehensive Overview ◽  
Or Efficiency

Early in vivo embryonic retinal development is a well-documented and evolutionary conserved process. The specification towards eye development is temporally controlled by consecutive activation or inhibition of multiple key signaling pathways, such as the Wnt and hedgehog signaling pathways. Recently, with the use of retinal organoids, researchers aim to manipulate these pathways to achieve better human representative models for retinal development and disease. To achieve this, a plethora of different small molecules and signaling factors have been used at various time points and concentrations in retinal organoid differentiations, with varying success. Additions differ from protocol to protocol, but their usefulness or efficiency has not yet been systematically reviewed. Interestingly, many of these small molecules affect the same and/or multiple pathways, leading to reduced reproducibility and high variability between studies. In this review, we make an inventory of the key signaling pathways involved in early retinogenesis and their effect on the development of the early retina in vitro. Further, we provide a comprehensive overview of the small molecules and signaling factors that are added to retinal organoid differentiation protocols, documenting the molecular and functional effects of these additions. Lastly, we comparatively evaluate several of these factors using our established retinal organoid methodology.

scholarly journals The Metabolic Effects of Angiopoietin-like protein 8 (ANGPLT8) are Differentially Regulated by Insulin and Glucose in Adipose Tissue and Liver and are Controlled by AMPK Signaling

2019 ◽  
Author(s):  
Lu Zhang ◽  
Chris E. Shannon ◽  
Terry M. Bakewell ◽  
Muhammad A. Abdul-Ghani ◽  
Marcel Fourcaudot ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Transcriptional Control ◽  
Metabolic Effects ◽  
Luciferase Reporter ◽  
Ampk Signaling ◽  
Insulin Clamp ◽  
Metabolic Role

AbstractObjectiveThe angiopoietin-like protein (ANGPTL) family represents a promising therapeutic target for dyslipidemia, which is a feature of obesity and type 2 diabetes (T2DM). The aim of the present study was to determine the metabolic role of ANGPTL8 and to investigate its nutritional, hormonal and molecular regulation in key metabolic tissues.MethodsThe metabolism of ANGPTL8 knockout mice (ANGPTL8−/−) was examined in mice following chow and high-fat diets (HFD). The regulation of ANGPTL8 expression by insulin and glucose was quantified using a combination of in vivo insulin clamp experiments in mice and in vitro experiments in hepatocytes and adipocytes. The role of AMPK signaling was examined, and the transcriptional control of ANGPTL8 was determined using bioinformatic and luciferase reporter approaches.ResultsThe ANGPTL8−/−mice had improved glucose tolerance and displayed reduced fed and fasted plasma triglycerides. However, there was no reduction in steatosis in ANGPTL8−/−mice after the HFD. Insulin acutely activated ANGPTL8 expression in liver and adipose tissue, which was mediated by C/EBPβ. Using insulin clamp experiments we observed that glucose further enhanced ANGPTL8 expression in the presence of insulin in adipocytes only. The activation of AMPK signaling potently suppressed the effect of insulin on ANGPTL8 expression in hepatocytes.ConclusionThese data show that ANGPTL8 plays an important metabolic role in mice that may extend beyond triglyceride metabolism. The finding that insulin and glucose have distinct roles in regulating ANGPTL8 expression in liver and adipose tissue may provide important clues about the function of ANGPTL8 in these tissues.

scholarly journals Collagen I Induces Preeclampsia-Like Symptoms by Suppressing Proliferation and Invasion of Trophoblasts

2021 ◽  
Vol 12 ◽  
Author(s):  
Yinglin Feng ◽  
Xia Chen ◽  
Huiqiao Wang ◽  
Xueping Chen ◽  
Zixin Lan ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Transcriptome Sequencing ◽  
Systolic Pressure ◽  
Histological Change ◽  
Collagen I ◽  
Erk Phosphorylation ◽  
Proliferation And Invasion

Preeclampsia is a common obstetric disorder affecting 2-8% of pregnancy worldwide. Fibrosis is an important histological change occurring in preeclamptic placenta, and might depend on the excess deposition of collagen I. However, the role of fibrotic placenta and collagen I in the pathogenesis of preeclampsia remains unclear. Therefore, we analyzed the collagen deposition and the expression of Collagen I in human placenta by Masson staining, Sirius red staining and western blotting. Further, the role of collagen I in preeclampsia pathogenesis was studied in C57BL/6 mice. HTR-8/SVneo cells were used to investigate the mechanisms underlying the effects of collagen I in trophoblasts by transcriptome sequencing and pharmacological agonists. Human preeclamptic placenta exhibited a significantly higher degree of fibrosis in stem villi and terminal villi than normal placenta, and was characterized by collagen I deposition. In vivo, a single injection of collagen I on gestational day 0.5 led to an increase in systolic pressure of pregnant mice from gestational days 4.5–17.5, to a decrease in weight and number of embryos, and to enhanced placental collagen I expression and degree of fibrosis compared with control mice. In vitro, collagen I attenuated the proliferation and invasion of HTR-8SV/neo cells. This effect could be reversed by treatment with agonists of ERK and β-catenin. Moreover, transcriptome sequencing demonstrated that signaling pathways related to cell proliferation and invasion were significantly downregulated in HTR-8SV/neo cells. Thus, we propose that collagen I induced preeclampsia-like symptoms by suppressing the proliferation and invasion of trophoblasts through inhibition of the ERK phosphorylation and WNT/β-catenin signaling pathways. Our findings could pave the way to the discovery of small-molecule inhibitors for preeclampsia treatment and future studies with larger sample size are required.

Regulation of ANGPTL8 in liver and adipose tissue by nutritional and hormonal signals and its effect on glucose homeostasis in mice

2020 ◽  
Vol 318 (5) ◽  
pp. E613-E624
Author(s):  
Lu Zhang ◽  
Chris E. Shannon ◽  
Terry M. Bakewell ◽  
Muhammad A. Abdul-Ghani ◽  
Marcel Fourcaudot ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Transcriptional Control ◽  
Luciferase Reporter ◽  
Ampk Signaling ◽  
Insulin Clamp ◽  
Metabolic Role ◽  
Promising Therapeutic Target

The angiopoietin-like protein (ANGPTL) family represents a promising therapeutic target for dyslipidemia, which is a feature of obesity and type 2 diabetes (T2DM). The aim of the present study was to determine the metabolic role of ANGPTL8 and to investigate its nutritional, hormonal, and molecular regulation in key metabolic tissues. The regulation of Angptl8 gene expression by insulin and glucose was quantified using a combination of in vivo insulin clamp experiments in mice and in vitro experiments in primary and cultured hepatocytes and adipocytes. The role of AMPK signaling was examined, and the transcriptional control of Angptl8 was determined using bioinformatic and luciferase reporter approaches. The metabolism of Angptl8 knockout mice (ANGPTL8−/−) was examined following chow and high-fat diets (HFD). Insulin acutely increased Angptl8 expression in liver and adipose tissue, which involved the CCAAT/enhancer-binding protein (C/EBPβ) transcription factor. In insulin clamp experiments, glucose further enhanced Angptl8 expression in the presence of insulin in adipose tissue. The activation of AMPK signaling antagonized the effect of insulin on Angptl8 expression in hepatocytes and adipocytes. The ANGPTL8−/− mice had improved glucose tolerance and displayed reduced fed and fasted plasma triglycerides. However, there was no change in body weight or steatosis in ANGPTL8−/− mice after the HFD. These data show that ANGPTL8 plays important metabolic roles in mice that extend beyond triglyceride metabolism. The finding that insulin, glucose, and AMPK signaling regulate Angptl8 expression may provide important clues about the distinct function of ANGPTL8 in these tissues.

scholarly journals Role of Flavonoids in the Prevention of AhR-Dependent Resistance During Treatment with BRAF Inhibitors

2020 ◽  
Vol 21 (14) ◽  
pp. 5025
Author(s):  
Héloïse M. Leclair ◽  
Nina Tardif ◽  
Anaïs Paris ◽  
Marie-Dominique Galibert ◽  
Sébastien Corre
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Therapeutic Potential ◽  
Progression Free Survival ◽  
Human Melanoma ◽  
Human Melanoma Cell ◽  
Melanoma Cell Lines

BRAF and MEK inhibitors (BRAFi and MEKi) are the standard of care for the treatment of metastatic melanoma in patients with BRAFV600E mutations, greatly improving progression-free survival. However, the acquisition of resistance to BRAFi and MEKi remains a difficult clinical challenge, with limited therapeutic options available for these patients. Here, we investigated the therapeutic potential of natural flavonoids as specific AhR (Aryl hydrocarbon Receptor) transcription factor antagonists in combination with BRAFi. Experimental Design: Experiments were performed in vitro and in vivo with various human melanoma cell lines (mutated for BRAFV600E) sensitive or resistant to BRAFi. We evaluated the role of various flavonoids on cell sensitivity to BRAFi and their ability to counteract resistance and the invasive phenotype of melanoma. Results: Flavonoids were highly effective in potentiating BRAFi therapy in human melanoma cell lines by increasing sensitivity and delaying the pool of resistant cells that arise during treatment. As AhR antagonists, flavonoids counteracted a gene expression program associated with the acquisition of resistance and phenotype switching that leads to an invasive and EMT-like phenotype. Conclusions: The use of natural flavonoids opens new therapeutic opportunities for the treatment of patients with BRAF-resistant disease.

scholarly journals ADAMTS5 in Osteoarthritis: Biological Functions, Regulatory Network, and Potential Targeting Therapies

2021 ◽  
Vol 8 ◽  
Author(s):  
Lejian Jiang ◽  
Jiachen Lin ◽  
Sen Zhao ◽  
Jiaqian Wu ◽  
Yongming Jin ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Biological Process ◽  
Therapeutic Strategies ◽  
Molecular Signaling ◽  
Biological Functions ◽  
Fundamental Understanding

ADAMTS5 is involved in the pathogenesis of OA. As the major aggrecanase-degrading articular cartilage matrix, ADAMTS5, has been regarded as a potential target for OA treatment. We here provide an updated insight on the regulation of ADAMTS5 and newly discovered therapeutic strategies for OA. Pathophysiological and molecular mechanisms underlying articular inflammation and mechanotransduction, as well as chondrocyte hypertrophy were discussed, and the role of ADAMTS5 in each biological process was reviewed, respectively. Senescence, inheritance, inflammation, and mechanical stress are involved in the overactivation of ADAMTS5, contributing to the pathogenesis of OA. Multiple molecular signaling pathways were observed to modulate ADAMTS5 expression, namely, Runx2, Fgf2, Notch, Wnt, NF-κB, YAP/TAZ, and the other inflammatory signaling pathways. Based on the fundamental understanding of ADAMTS5 in OA pathogenesis, monoclonal antibodies and small molecule inhibitors against ADAMTS5 were developed and proved to be beneficial pre-clinically both in vitro and in vivo. Recent novel RNA therapies demonstrated potentials in OA animal models. To sum up, ADAMTS5 inhibition and its signaling pathway–based modulations showed great potential in future therapeutic strategies for OA.

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