scholarly journals JAG1 intracellular domain acts as a transcriptional cofactor that forms an oncogenic transcriptional complex with DDX17/SMAD3/TGIF2

2021 ◽  
Author(s):  
Eun-Jung Kim ◽  
Jung Yun Kim ◽  
Sung-Ok Kim ◽  
Seok Won Ham ◽  
Sang-Hun Choi ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Tumor Formation ◽  
Intracellular Domain ◽  
Notch Ligand ◽  
Chip Sequencing ◽  
Sox2 Expression ◽  
Notch Receptors ◽  
Transcriptional Complex ◽  
Resistance To Chemotherapy

Jagged1 (JAG1) is a Notch ligand that contact-dependently activates Notch receptors and regulates cancer progression. The JAG1 intracellular domain (JICD1) is generated from JAG1, such as the formation of NOTCH1 intracellular domain (NICD1), however, the role of JICD1 in tumorigenicity has not been comprehensively elucidated. Herein, we revealed that JICD1 induced astrocytes to acquire several cancer stem cell properties, including tumor formation, invasiveness, stemness, and resistance to chemotherapy and radiotherapy. The transcriptome, ChIP-sequencing, and proteomic analyses revealed that JICD1 increased SOX2 expression by forming a transcriptional complex with DDX17, SMAD3, and TGIF2. Furthermore, JICD1-driven tumorigenicity was directly regulated by SOX2. Therefore, our results demonstrated that, like NICD1, JICD1 acts as a transcriptional cofactor in the formation of the DDX17/SMAD3/TGIF2 transcriptional complex, leading to oncogenic transformation.

scholarly journals Role of the V1G1 subunit of V-ATPase in breast cancer cell migration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria De Luca ◽  
Roberta Romano ◽  
Cecilia Bucci
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Motility ◽  
Cancer Progression ◽  
Tumor Formation ◽  
Downstream Signaling ◽  
Late Endosomes ◽  
Intracellular Compartments

AbstractV-ATPase is a large multi-subunit complex that regulates acidity of intracellular compartments and of extracellular environment. V-ATPase consists of several subunits that drive specific regulatory mechanisms. The V1G1 subunit, a component of the peripheral stalk of the pump, controls localization and activation of the pump on late endosomes and lysosomes by interacting with RILP and RAB7. Deregulation of some subunits of the pump has been related to tumor invasion and metastasis formation in breast cancer. We observed a decrease of V1G1 and RAB7 in highly invasive breast cancer cells, suggesting a key role of these proteins in controlling cancer progression. Moreover, in MDA-MB-231 cells, modulation of V1G1 affected cell migration and matrix metalloproteinase activation in vitro, processes important for tumor formation and dissemination. In these cells, characterized by high expression of EGFR, we demonstrated that V1G1 modulates EGFR stability and the EGFR downstream signaling pathways that control several factors required for cell motility, among which RAC1 and cofilin. In addition, we showed a key role of V1G1 in the biogenesis of endosomes and lysosomes. Altogether, our data describe a new molecular mechanism, controlled by V1G1, required for cell motility and that promotes breast cancer tumorigenesis.

scholarly journals Signaling Pathways Regulating TC21-induced Tumorigenesis

2007 ◽  
Vol 282 (38) ◽  
pp. 27713-27720 ◽  
Author(s):  
Mete Erdogan ◽  
Ambra Pozzi ◽  
Neil Bhowmick ◽  
Harold L Moses ◽  
Roy Zent
Keyword(s):  
P38 Mapk ◽  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Cellular Transformation ◽  
Tumor Formation ◽  
Transformed Cells ◽  
Growth Inhibitory ◽  
Phosphoinositide 3 Kinase

TC21(R-Ras2), a Ras-related GTPase with transforming potential similar to H-, K- and N-Ras, is implicated in the pathogenesis of human cancers. Transforming growth factor β (TGF-β), a cytokine that plays a significant role in modulating tumorigenesis, normally prevents uncontrolled cell proliferation but paradoxically induces proliferation in H-Ras-transformed cancer cells. Although TC21 activates some pathways that mediate cellular transformation by the classical Ras proteins, the mechanisms through which TC21 induces tumor formation and how TGF-β regulates TC21 transformed cells is not known. To better understand the role of TC21 in cancer progression, we overexpressed an activated G23V mutant of TC21 in a nontumorigenic murine mammary epithelial (EpH4) cell line. Mutant TC21-expressing cells were significantly more oncogenic than cells expressing activated G12V H-Ras both in vivo and in vitro. TC21-induced transformation and proliferation required activation of p38 MAPK, mTOR (the mammalian target of rapamycin), and phosphoinositide 3-kinase but not Akt/PKB. Transformation by TC21 rendered EpH4 cells insensitive to the growth inhibitory effects of TGF-β, and the soft agar growth of these cells was increased upon TGF-β stimulation. Despite losing responsiveness to TGF-β-mediated growth inhibition, both Smad-dependent and independent pathways remained intact in TC21-transformed cells. Thus, overexpression of active TC21 in EpH4 cells induces tumorigenicity through the phosphoinositide 3-kinase, p38 MAPK, and mTOR pathways, and these cells lose their sensitivity to the normal growth inhibitory role of TGF-β.

scholarly journals The Role of Cavin3 in the Progression of Lung Cancer and Its Mechanism

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Gaozhong Sun ◽  
Kewei Ni
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Tumor Formation ◽  
Migration And Invasion ◽  
Clinical Value ◽  
Promote Cell Proliferation ◽  
Cancer Tissues

Objective. The purpose of this study was to describe the role of Cavin3 in the progression of lung cancer and its underlying mechanism. Methods. Totally, 200 cases of lung cancer tissues and corresponding paracancer tissues were collected. Cavin3 expression in samples was determined by qRT-PCR, and the correlation with lung cancer stages as well as prognosis was statistically analyzed combined with matched clinical information. To investigate the mechanism of Cavin3 in lung cancer progression, firstly, Cavin3 was detected in lung cancer cell lines A549, PC9, and H520. Then, cells with stable Cavin3 overexpression and Cavin3 knockout were established to determine the effect of Cavin3 overexpression on the mammalian target of rapamycin (mTOR) signaling pathway. Subsequently, cells were harvested for cell proliferation, migration, and invasion assays in vitro, as well as nude mouse transplantation tumor experiment in vivo. Results. Cavin3 was seen to be highly expressed in cancer tissues. Statistical analysis with matched clinical data showed that Cavin3 as a prognostic indicator of lung cancer had important clinical value. In addition, it could be found that high expression of Cavin3 was able to promote cell proliferation, migration, and invasion and also potentiate tumor formation in vivo. Conclusion. Cavin3 was highly expressed in lung cancer, and it was capable to promote cell proliferation, invasion, and migration.

scholarly journals Downregulation of the ubiquitin ligase KBTBD8 prevented epithelial ovarian cancer progression

2020 ◽  
Vol 26 (1) ◽  
Author(s):  
Lei Du ◽  
Cong-Rong Li ◽  
Qi-Feng He ◽  
Xiao-Hua Li ◽  
Lin-Fei Yang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Rna Sequencing ◽  
Cancer Progression ◽  
Tumor Formation ◽  
Tumor Xenograft ◽  
Healthy Growth ◽  
And Migration

Abstract Objectives Kelch repeat and BTB domain-containing protein 8, KBTBD8, has been identified as a female fertility factor. However, there have been no reports on the role of KBTBD8 in the progression of epithelial ovarian cancer, EOC. Our study aimed to address this issue. Methods We first examine KBTBD8 expression in EOC tissues and cells. Next, we performed RNA sequencing to reveal the overall mechanism. Then we investigated the roles of KBTBD8 in the proliferation, migration, and health status of cultured EOC cells. Finally, we employed tumor xenograft models to evaluate the role of KBTBD8 in vivo. Results First, KBTBD8 level was significantly higher in EOC tissues and cells. Next, comparative RNA sequencing identified more tumorigenesis-related genes that KBTBD8 might regulate. Then we found that KBTBD8 knockdown significantly decreased EOC cell proliferation, migration, and the activities of multiple tumorigenesis-related kinases. Finally, KBTBD8 knockdown significantly diminished ovarian tumor formation in vivo. Conclusion Proper KBTBD8 level is essential for the healthy growth of ovarian somatic cells, such as ovarian epithelial cells. Excessive KBTBD8 might be a significant impetus for EOC progression. KBTBD8 reduction greatly inhibits EOC proliferation and migration.

scholarly journals Beyond Tumor Suppression: Senescence in Cancer Stemness and Tumor Dormancy

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 346 ◽  
Author(s):  
Francisco Triana-Martínez ◽  
María Isabel Loza ◽  
Eduardo Domínguez
Keyword(s):  
Cell Fate ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Tumor Development ◽  
Tumor Formation ◽  
Cell Fates ◽  
Synthetic Lethal ◽  
Cell Phenotypes ◽  
The Impact

Here, we provide an overview of the importance of cellular fate in cancer as a group of diseases of abnormal cell growth. Tumor development and progression is a highly dynamic process, with several phases of evolution. The existing evidence about the origin and consequences of cancer cell fate specification (e.g., proliferation, senescence, stemness, dormancy, quiescence, and cell cycle re-entry) in the context of tumor formation and metastasis is discussed. The interplay between these dynamic tumor cell phenotypes, the microenvironment, and the immune system is also reviewed in relation to cancer. We focus on the role of senescence during cancer progression, with a special emphasis on its relationship with stemness and dormancy. Selective interventions on senescence and dormancy cell fates, including the specific targeting of cancer cell populations to prevent detrimental effects in aging and disease, are also reviewed. A new conceptual framework about the impact of synthetic lethal strategies by using senogenics and then senolytics is given, with the promise of future directions on innovative anticancer therapies.

scholarly journals ETMR-03. THE ROLE OF FOXR2 IN PEDIATRIC BRAIN CANCER

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii323-iii323
Author(s):  
Felix Schmitt-Hoffner ◽  
Sjoerd van Rijn ◽  
Jens-Martin Hübner ◽  
Sander Lambo ◽  
Monika Mauermann ◽  
...  
Keyword(s):  
Pediatric Brain Tumors ◽  
Tumor Formation ◽  
Human Neural Stem Cells ◽  
Chip Sequencing ◽  
Nsg Mice ◽  
Forkhead Box ◽  
Neuroectodermal Tumors ◽  
The Central Nervous System ◽  
Pediatric Brain

Abstract Forkhead Box R2 (FOXR2) is a transcription factor of the Forkhead Box family that has been correlated with tumorigenesis, aberrant cell growth or tumor progression. Expression of FOXR2 in pediatric brain tumors is, besides in subsets of medullo-, pineo- and glioblastoma, primarily present in CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2), a novel entity that we in 2016 identified from the former class of primitive neuroectodermal tumors of the central nervous system (CNS-PNET). Analyzing CNS-NB-FOXR2 tumors we found that FOXR2 mRNA is expressed in an anti-correlative manner compared to the proto-oncogenes MYC and MYCN. With immunoprecipitation analyses we show that FOXR2 binds to MYC and MYCN and is thereby stabilizing these proteins. These observations on the interaction and the anti-correlative manner suggest that FOXR2 and MYC(N) may drive tumor formation in a molecularly similar fashion. To investigate this further we stably expressed FOXR2, MYCN and MYC and a combination of FOXR2 with MYC(N) in human neural stem cells (hNSC) and injected these in the striatum of NSG mice. We could show that hNSC itself do not from a tumor, whereas the expression of FOXR2 and/or MYC(N) in hNSC results in tumorigenesis. Tumors expressing both, FOXR2 and MYC(N) were growing faster than tumors with FOXR2 alone. In addition, tumors are currently being analyzed by ChIP-sequencing for FOXR2, MYC, and MYCN, to better understand the mechanisms how FOXR2 drives tumor formation compared to its interaction partners MYC and MYCN.

scholarly journals The Notch Pathway in Breast Cancer Progression

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Emmanuel N. Kontomanolis ◽  
Sofia Kalagasidou ◽  
Stamatia Pouliliou ◽  
Xanthoula Anthoulaki ◽  
Nikolaos Georgiou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Breast Cancer Progression ◽  
Notch Receptors ◽  
The Impact

Objective. Notch signaling pathway is a vital parameter of the mammalian vascular system. In this review, the authors summarize the current knowledge about the impact of the Notch signaling pathway in breast cancer progression and the therapeutic role of Notch’s inhibition.Methods. The available literature in MEDLINE, PubMed, and Scopus, regarding the role of the Notch pathway in breast cancer progression was searched for related articles from about 1973 to 2017 including terms such as “Notch,” “Breast Cancer,” and “Angiogenesis.”Results. Notch signaling controls the differentiation of breast epithelial cells during normal development. Studies confirm that the Notch pathway has a major participation in breast cancer progression through overexpression and/or abnormal genetic type expression of the notch receptors and ligands that determine angiogenesis. The cross-talk of Notch and estrogens, the effect of Notch in breast cancer stem cells formation, and the dependable Notch overexpression during breast tumorigenesis have been studied enough and undoubtedly linked to breast cancer development. The already applied therapeutic inhibition of Notch for breast cancer can drastically change the course of the disease.Conclusion. Current data prove that Notch pathway has a major participation and multiple roles during breast tumor progression. Inhibition of Notch receptors and ligands provides innovative therapeutic results and could become the therapy of choice in the next few years, even though further research is needed to reach safe conclusions.

scholarly journals Circ-GALNT16 restrains colorectal cancer progression by enhancing the SUMOylation of hnRNPK

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Chaofan Peng ◽  
Yuqian Tan ◽  
Peng Yang ◽  
Kangpeng Jin ◽  
Chuan Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Binding ◽  
Rna Sequencing ◽  
Cancer Progression ◽  
Transcriptional Level ◽  
Binding Ability ◽  
Transcriptional Complex

Abstract Background Recent studies have investigated the role of circular RNAs (circRNAs) as significant regulatory factors in multiple cancer progression. Nevertheless, the biological functions of circRNAs and the underlying mechanisms by which they regulate colorectal cancer (CRC) progression remain unclear. Methods A novel circRNA (circ-GALNT16) was identified by microarray and qRT-PCR. A series of in vitro and in vivo phenotype experiments were performed to investigate the role of circ-GALNT16 in CRC. The FISH, RNA pulldown assay, RIP assay, RNA sequencing, coimmunoprecipitation, and ChIP were performed to investigate the molecular mechanisms of circ-GALNT16 in CRC progression. Results Circ-GALNT16 was downregulated in CRC and was negatively correlated with poor prognosis. Circ-GALNT16 suppressed the proliferation and metastatic ability of CRC cells in vitro and in vivo. Mechanistically, circ-GALNT16 could bind to the KH3 domain of heterogeneous nuclear ribonucleoprotein K (hnRNPK), which promoted the SUMOylation of hnRNPK. Additionally, circ-GALNT16 could enhance the formation of the hnRNPK-p53 complex by facilitating the SUMOylation of hnRNPK. RNA sequencing assay identified serpin family E member 1 as the target gene of circ-GALNT16 at the transcriptional level. Rescue assays revealed that circ-GALNT16 regulated the expression of Serpine1 by inhibiting the deSUMOylation of hnRNPK mediated by SUMO-specific peptidase 2 and then regulating the sequence-specific DNA binding ability of the hnRNPK-p53 transcriptional complex. Conclusions Circ-GALNT16 suppressed CRC progression by inhibiting Serpine1 expression through regulating the sequence-specific DNA binding ability of the SENP2-mediated hnRNPK-p53 transcriptional complex and might function as a biomarker and therapeutic target for CRC.

scholarly journals The Potential Role of Changes in the Glucose and Lipid Metabolic Pathways in Gastrointestinal Cancer Progression: Strategy in Cancer Therapy

2021 ◽  
pp. 1-8
Author(s):  
Gordon A. Ferns ◽  
Milad Shahini Shams Abadi ◽  
Ahmad Raeisi ◽  
Mohammad-Hassan Arjmand
Keyword(s):  
Cancer Progression ◽  
Metabolic Pathways ◽  
Cell Metabolism ◽  
Tumor Formation ◽  
High Rate ◽  
Metabolic Inhibitors ◽  
Chemotherapy Drugs ◽  
Poor Outcomes ◽  
Rate Limiting

<b><i>Background:</i></b> Changes in cell metabolism are a well-known feature of some cancers, and this may be involved in the etiology of tumor formation and progression, as well as tumor heterogeneity. These changes may affect fatty acid metabolism and glycolysis and are required to provide the increase in energy necessary for the high rate of proliferation of cancer cells. Gastrointestinal cancers remain a difficult-to-treat cancer, particularly as they are usually diagnosed at a late stage of disease and are associated with poor outcomes. <b><i>Summary:</i></b> Recently, the changes in the metabolic pathways, including the expression of the rate-limiting enzymes involved, have been considered to be a potential target for therapy for gastrointestinal tumors. <b><i>Key Message:</i></b> A combination of routine chemotherapy drugs with metabolic inhibitors may improve the effectiveness of treatment.

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