scholarly journals Cellular Senescence: Many Roads, One Final Destination

2010 ◽  
Vol 10 ◽  
pp. 727-741 ◽  
Author(s):  
Raya Saab
Keyword(s):  
Tumor Suppressor ◽  
Cellular Senescence ◽  
Short Review ◽  
Premalignant Lesions ◽  
Telomere Shortening ◽  
Final Destination ◽  
Suppressor Mechanism ◽  
Oncogenic Stress

Cellular senescence is a tumor-suppressor mechanism that has been shown to occur in response to multiple signals, including oncogenic stress, DNA damage, oxidative stress, telomere shortening, and other tumor-promoting insults. Over the past decade, much has been uncovered regarding the phenotype of this tumor-suppressor response and the underlying pathways necessary for its establishment. However, we have also learned that the intricate details of signaling pathways underlying senescence as a tumor-suppressor response are very much context dependent. In addition, cross-talk among pathways, and negative and positive feedback loops, all complicate our understanding of this process. This short review attempts to summarize what is known to date regarding senescence in tumor suppression, bothin vitroandin vivo. Further insights into pathways necessary for senescence will hopefully identify appropriate targets for interventions to not only induce senescence as a treatment of cancerous lesions, but also to maintain this state in premalignant lesions in an effort to prevent progression to cancer.

iTSP-PseAAC: Identify Tumor Suppressor Proteins by Using Fully Connected Neural Network and PseAAC

2021 ◽  
Vol 15 ◽  
Author(s):  
Muhammad Awais ◽  
Waqar Hussain ◽  
Nouman Rasool ◽  
Yaser Daanial Khan
Keyword(s):  
Tumor Suppressor ◽  
Cross Validation ◽  
Control Cell ◽  
Normal Function ◽  
In Vivo Studies ◽  
Tumor Suppressor Proteins ◽  
Proposed Model ◽  
Self Consistency

Background: The uncontrolled growth due to accumulation of genetic and epigenetic changes as a result of loss or reduction in the normal function of Tumor Suppressor Genes (TSGs) and Pro-oncogenes is known as cancer. TSGs control cell division and growth by repairing of DNA mistakes during replication and restrict the unwanted proliferation of a cell or activities, those are the part of tumor production. Objectives: This study aims to propose a novel, accurate, user-friendly model to predict tumor suppressor proteins, which would be freely available to experimental molecular biologists to assist them using in vitro and in vivo studies. Methods: The predictor model has used the input feature vector (IFV) calculated from the physicochemical properties of proteins based on FCNN to compute the accuracy, sensitivity, specificity, and MCC. The proposed model was validated against different exhaustive validation techniques i.e. self-consistency and cross-validation. Results: Using self-consistency, the accuracy is 99%, for cross-validation and independent testing has 99.80% and 100% accuracy respectively. The overall accuracy of the proposed model is 99%, sensitivity value 98% and specificity 99% and F1-score was 0.99. Conclusion: It concludes, the proposed model for prediction of the tumor suppressor proteins can predict the tumor suppressor proteins efficiently, but it still has space for improvements in computational ways as the protein sequences may rapidly increase, day by day.

scholarly journals Weakly Acidic Bile Is a Risk Factor for Hypopharyngeal Carcinogenesis Evidenced by DNA Damage, Antiapoptotic Function, and Premalignant Dysplastic Lesions In Vivo

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 852 ◽  
Author(s):  
Clarence T. Sasaki ◽  
Sotirios G. Doukas ◽  
Panagiotis G. Doukas ◽  
Dimitra P. Vageli
Keyword(s):  
Premalignant Lesions ◽  
Acidic Ph ◽  
Upper Aerodigestive Tract ◽  
Carcinogenic Effect ◽  
Secondary Bile Acid ◽  
P53 Expression ◽  
Refractory Gerd ◽  
Antacid Therapy

Background: There is recent in vivo discovery documenting the carcinogenic effect of bile at strongly acidic pH 3.0 in hypopharynx, while in vitro data demonstrate that weakly acidic bile (pH 5.5) has a similar oncogenic effect. Because esophageal refluxate often occurs at pH > 4.0, here we aim to determine whether weakly acidic bile is also carcinogenic in vivo. Methods: Using 32 wild-type mice C57B16J, we performed topical application of conjugated primary bile acids with or without unconjugated secondary bile acid, deoxycholic acid (DCA), at pH 5.5 and controls, to hypopharyngeal mucosa (HM) twice per day, for 15 weeks. Results: Chronic exposure of HM to weakly acidic bile, promotes premalignant lesions with microinvasion, preceded by significant DNA/RNA oxidative damage, γH2AX (double strand breaks), NF-κB and p53 expression, overexpression of Bcl-2, and elevated Tnf and Il6 mRNAs, compared to controls. Weakly acidic bile, without DCA, upregulates the “oncomirs”, miR-21 and miR-155. The presence of DCA promotes Egfr, Wnt5a, and Rela overexpression, and a significant downregulation of “tumor suppressor” miR-451a. Conclusion: Weakly acidic pH increases the risk of bile-related hypopharyngeal neoplasia. The oncogenic properties of biliary esophageal reflux on the epithelium of the upper aerodigestive tract may not be fully modified when antacid therapy is applied. We believe that due to bile content, alternative therapeutic strategies using specific inhibitors of relevant molecular pathways or receptors may be considered in patients with refractory GERD.

scholarly journals Calcium channel ITPR2 and mitochondria–ER contacts promote cellular senescence and aging

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dorian V. Ziegler ◽  
David Vindrieux ◽  
Delphine Goehrig ◽  
Sara Jaber ◽  
Guillaume Collin ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Calcium Release ◽  
Liver Steatosis ◽  
Metabolic Stress ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Age Related ◽  
Trisphosphate Receptor

AbstractCellular senescence is induced by stresses and results in a stable proliferation arrest accompanied by a pro-inflammatory secretome. Senescent cells accumulate during aging, promoting various age-related pathologies and limiting lifespan. The endoplasmic reticulum (ER) inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) calcium-release channel and calcium fluxes from the ER to the mitochondria are drivers of senescence in human cells. Here we show that Itpr2 knockout (KO) mice display improved aging such as increased lifespan, a better response to metabolic stress, less immunosenescence, as well as less liver steatosis and fibrosis. Cellular senescence, which is known to promote these alterations, is decreased in Itpr2 KO mice and Itpr2 KO embryo-derived cells. Interestingly, ablation of ITPR2 in vivo and in vitro decreases the number of contacts between the mitochondria and the ER and their forced contacts induce premature senescence. These findings shed light on the role of contacts and facilitated exchanges between the ER and the mitochondria through ITPR2 in regulating senescence and aging.

scholarly journals Tumor Suppressor Function of miR-127-3p and miR-376a-3p in Osteosarcoma Cells

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2019 ◽  
Author(s):  
Joerg Fellenberg ◽  
Burkhard Lehner ◽  
Heiner Saehr ◽  
Astrid Schenker ◽  
Pierre Kunz
Keyword(s):  
Tumor Suppressor ◽  
Therapeutic Strategies ◽  
High Dose ◽  
Osteosarcoma Cell ◽  
Tumor Suppressor Function ◽  
Osteosarcoma Cells ◽  
Aberrant Expression ◽  
Suppressor Function

Since the introduction of high-dose chemotherapy about 35 years ago, survival rates of osteosarcoma patients have not been significantly improved. New therapeutic strategies replacing or complementing conventional chemotherapy are therefore urgently required. MicroRNAs represent promising targets for such new therapies, as they are involved in the pathology of multiple types of cancer, and aberrant expression of several miRNAs has already been shown in osteosarcoma. In this study, we identified silencing of miR-127-3p and miR-376a-3p in osteosarcoma cell lines and tissues and investigated their role as potential tumor suppressors in vitro and in vivo. Transfection of osteosarcoma cells (n = 6) with miR-127-3p and miR-376a-3p mimics significantly inhibited proliferation and reduced the colony formation capacity of these cells. In contrast, we could not detect any influence of miRNA restoration on cell cycle and apoptosis induction. The effects of candidate miRNA restoration on tumor engraftment and growth in vivo were analyzed using a chicken chorioallantoic membrane (CAM) assay. Cells transfected with mir-127-3p and miR-376a-3p showed reduced tumor take rates and tumor volumes and a significant decrease of the cumulative tumor volumes to 41% and 54% compared to wildtype cells. The observed tumor suppressor function of both analyzed miRNAs indicates these miRNAs as potentially valuable targets for the development of new therapeutic strategies for the treatment of osteosarcoma.

scholarly journals Hypermethylation of DHRS3 as a Novel Tumor Suppressor Involved in Tumor Growth and Prognosis in Gastric Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Sha Sumei ◽  
Kong Xiangyun ◽  
Chen Fenrong ◽  
Sun Xueguang ◽  
Hu Sijun ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Suppressor ◽  
Tumor Growth ◽  
Human Cancer ◽  
Methylation Status ◽  
Ectopic Expression ◽  
Survival Times

Background/AimsThe role of DHRS3 in human cancer remains unclear. Our study explored the role of DHRS3 in gastric cancer (GC) and its clinicopathological significance and associated mechanisms.MaterialsBisulfite-assisted genomic sequencing PCR and a Mass-Array system were used to evaluate and quantify the methylation levels of the promoter. The expression levels and biological function of DHRS3 was examined by both in vitro and in vivo assays. A two-way hierarchical cluster analysis was used to classify the methylation profiles, and the correlation between the methylation status of the DHRS3 promoter and the clinicopathological characteristics of GC were then assessed.ResultsThe DHRS3 promoter was hypermethylated in GC samples, while the mRNA and protein levels of DHRS3 were significantly downregulated. Ectopic expression of DHRS3 in GC cells inhibited cell proliferation and migration in vitro, decreased tumor growth in vivo. DHRS3 methylation was correlated with histological type and poor differentiation of tumors. GC patients with high degrees of CpG 9.10 methylation had shorter survival times than those with lower methylation.ConclusionDHRS3 was hypermethylated and downregulated in GC patients. Reduced expression of DHRS3 is implicated in gastric carcinogenesis, which suggests DHRS3 is a tumor suppressor.

scholarly journals Μελέτη της κυτταρικής γήρανσης στον ομαλό λειχήνα του στόματος με τη χρήση της ειδικής χρώσης της λιποφουσκίνης με sudan black B, μιά πρωτότυπη μέθοδο ανίχνευσης γηρασμένων κυττάρων

2014 ◽  
Author(s):  
Ελένη Γεωργακοπούλου
Keyword(s):  
Cellular Senescence ◽  
Replicative Senescence ◽  
Sudan Black B ◽  
Beta Galactosidase

Ως κυτταρική γήρανση (cellular senescence) ορίζεται η μη αναστρέψιμη παύση του κυτταρικού κύκλου συνεπεία είτε εξάντλησης των τελομερών, είτε κυτταρικού στρες, και θεωρείται μηχανισμός αντίστασης στην καρκινογένεση. Το φαινόμενο της κυτταρικής γήρανσης αποτελεί μια ερευνητική πρόκληση μιας και αποτελεί συνδετικό κρίκο μεταξύ της φυσιολογικής γήρανσης της χρόνιας φλεγμονής και βασικών μονοπατιών της καρκινογένεσης. Ο μέχρι σήμερα πιο αξιόπιστος δείκτης κυτταρικής γήρανσης είναι η ανίχνευση της δραστηριότητας της β- γαλακτοσιδάσης των γηρασμένων κυττάρων ,(senescence-associated-beta-galactosidase SA-β-gal). Η μέθοδος αυτή δεν μπορεί να εφαρμοστεί σε αρχειακό υλικό (ιστούς εγκιβωτισμένους σε παραφίνη) αλλά μόνο σε φρέσκους ιστούς και σε τομές από άμεσα κατεψυγμένους ιστούς (κρυοτομές). Εξαιτίας αυτού του περιορισμού υπάρχει έλλειψη εκτενών κλινικοπαθολογικών μελετών για την κυτταρική γήρανση.ΣΚΟΠΟΣ : Επιχειρήθηκε η αναζήτηση ενός βιολογικού δείκτη κυτταρικής γήρανσης, με εφαρμογή σε αρχειακό υλικό. Επίσης, μελετήθηκε η πρωτότυπη χρησιμοποίησή του ως δείκτη κυτταρικής γήρανσης σε ένα χρόνιο φλεγμονώδες νόσημα που αποτελεί μοντέλο συσχέτισης χρόνιας φλεγμονής και καρκίνου, τον Ομαλό λειχήνα του στόματος.ΥΛΙΚΑ ΚΑΙ ΜΕΘΟΔΟΙ : Αναζητώντας μια μέθοδο ανίχνευσης γηρασμένων κυττάρων εφαρμόσιμη σε αρχειακό υλικό, αξιολογήσαμε την ιστοχημική χρώση Sudan-Black B (SBB), που είναι ειδική για την ανίχνευση της λιποφουσκίνης. Η λιποφουσκίνη είναι ένα συσσωμάτωμα οξειδωμένων πρωτεϊνών, λιπιδίων και μετάλλων, η οποία συσσωρεύεται σε γηρασμένους ιστούς. Αναλύσαμε κυτταρικά συστήματα στα οποία προκλήθηκε κυτταρική γήρανση είτε ύστερα από εξάντληση του πολλαπλασιασμού (replicative senescence) ή από στρεσογόνα ερεθίσματα, προ-καρκινικές αλλοιώσεις σε υπό προϋποθέσεις knock-in ποντίκια που παρουσιάζουν γήρανση, και τέλος σε ανθρώπινες προκαρκινικές αλλοιώσεις που γνωρίζουμε ότι περιέχουν γηρασμένα κύτταρα. Η τεχνική εν συνεχεία εφαρμόστηκε σε δείγματα Ομαλού λειχήνα, Ακανθοκυτταρικού καρκινώματος στόματος , καλοήθεις βλάβες στοματικού βλεννογόνου (ινώματα) και φυσιολογικού στοματικού βλεννογόνου.ΑΠΟΤΕΛΕΣΜΑΤΑ : Στα παραπάνω πειράματα αποδείξαμε την συνταύτιση της λιποφουσκίνης και του SA-β-gal σε in vitro και in vivo γηρασμένα κύττταρα (κατεψυγμένους ιστούς). Tα ευρήματα αυτά συνηγορούν πως η λιποφουσκίνη είναι ένας ικανός υποψήφιος δείκτης κυτταρικής γήρανσης. Επιπρόσθετα, κατεψυγμένοι ιστοί θετικοί για SA-β-gal μονιμοποιήθηκαν σε φορμόλη, εγκλείστηκαν σε παραφίνη και βάφτηκαν με SBB. Οι αντίστοιχες SA-β-gal θετικές περιοχές στον ιστό βάφτηκαν ειδικά για λιποφουσκίνη με SBB, ενώ οι ιστοί που ήταν αρνητικοί για SA-β-gal βρέθηκαν και αρνητικοί για τη λιποφουσκίνη. Τα ευρήματα αυτά ενισχύουν περαιτέρω την ευαισθησία και την ειδικότητα της SBB χρώσης για την ανάδειξη γηρασμένων κυττάρων σε αρχειακό υλικό. Η τελευταία μοναδική ιδιότητα του SBB μπορεί να αξιοποιηθεί για κλινικοπαθολογικές μελέτες στο ευρέως διαθέσιμο αρχειακό υλικό. Επιπρόσθετα, η εφαρμογή της τεχνικής σε τομές παραφίνης από Ομαλό λειχήνα, Ακανθοκυτταρικό καρκίνωμα σε ινώματα και φυσιολογικό ιστό στόματος, ανέδειξε την παρουσία γηρασμένων ινοβλαστών στις τομές των ινωμάτων και του Ομαλού λειχήνα και την απουσία τους στο φυσιολογικό ιστό και το Ακανθοκυτταρικό καρκίνωμα του στόματος. Τα ευρήματα αυτά συνηγορούν υπερ μιας προστατευτικής δράσης αυτών των κυττάρων , πιθανά στα πλαίσια μιας καλοήθους αντίδρασης του στρώματος.

scholarly journals Loss of SATB1 Induces a p21 Dependent Cellular Senescence Phenotype in Dopaminergic Neurons

2018 ◽  
Author(s):  
Markus Riessland ◽  
Benjamin Kolisnyk ◽  
Tae Wan Kim ◽  
Jia Cheng ◽  
Jason Ni ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cellular Senescence ◽  
Dopaminergic Neurons ◽  
Dna Binding Protein ◽  
Dopamine Neurons ◽  
Human Stem Cell ◽  
Transcriptional Program

AbstractCellular senescence is a mechanism used by mitotic cells to prevent uncontrolled cell division. As senescent cells persist in tissues, they cause local inflammation and are harmful to surrounding cells, contributing to aging. Generally, neurodegenerative diseases, such as Parkinson‘s, are disorders of aging. The contribution of cellular senescence to neurodegeneration is still unclear. SATB1 is a DNA binding protein associated with Parkinson’s disease. We report that SATB1 prevents cellular senescence in post-mitotic dopaminergic neurons. Loss of SATB1 causes activation of a cellular senescence transcriptional program in dopamine neurons, both in human stem cell-derived dopaminergic neurons and in mice. We observed phenotypes which are central to cellular senescence in SATB1 knockout dopamine neurons in vitro and in vivo. Moreover, we found that SATB1 directly represses expression of the pro-senescence factor, p21, in dopaminergic neurons. Our data implicate senescence of dopamine neurons as a contributing factor to the pathology of Parkinson’s disease.

scholarly journals Transcriptional role of p53 in interferon-mediated antiviral immunity

2008 ◽  
Vol 205 (8) ◽  
pp. 1929-1938 ◽  
Author(s):  
César Muñoz-Fontela ◽  
Salvador Macip ◽  
Luis Martínez-Sobrido ◽  
Lauren Brown ◽  
Joseph Ashour ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Viral Replication ◽  
Viral Infections ◽  
Suppressor Gene ◽  
Central Component ◽  
Type I ◽  
Infected Cells

Tumor suppressor p53 is activated by several stimuli, including DNA damage and oncogenic stress. Previous studies (Takaoka, A., S. Hayakawa, H. Yanai, D. Stoiber, H. Negishi, H. Kikuchi, S. Sasaki, K. Imai, T. Shibue, K. Honda, and T. Taniguchi. 2003. Nature. 424:516–523) have shown that p53 is also induced in response to viral infections as a downstream transcriptional target of type I interferon (IFN) signaling. Moreover, many viruses, including SV40, human papillomavirus, Kaposi's sarcoma herpesvirus, adenoviruses, and even RNA viruses such as polioviruses, have evolved mechanisms designated to abrogate p53 responses. We describe a novel p53 function in the activation of the IFN pathway. We observed that infected mouse and human cells with functional p53 exhibited markedly decreased viral replication early after infection. This early inhibition of viral replication was mediated both in vitro and in vivo by a p53-dependent enhancement of IFN signaling, specifically the induction of genes containing IFN-stimulated response elements. Of note, p53 also contributed to an increase in IFN release from infected cells. We established that this p53-dependent enhancement of IFN signaling is dependent to a great extent on the ability of p53 to activate the transcription of IFN regulatory factor 9, a central component of the IFN-stimulated gene factor 3 complex. Our results demonstrate that p53 contributes to innate immunity by enhancing IFN-dependent antiviral activity independent of its functions as a proapoptotic and tumor suppressor gene.

Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer

1992 ◽  
Vol 12 (3) ◽  
pp. 1387-1395
Author(s):  
M C Goyette ◽  
K Cho ◽  
C L Fasching ◽  
D B Levy ◽  
K W Kinzler ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Loss Of Function ◽  
Chromosome 18 ◽  
Chromosome 5 ◽  
Suppressor Genes ◽  
Single Defect

Carcinogenesis is a multistage process that has been characterized both by the activation of cellular oncogenes and by the loss of function of tumor suppressor genes. Colorectal cancer has been associated with the activation of ras oncogenes and with the deletion of multiple chromosomal regions including chromosomes 5q, 17p, and 18q. Such chromosome loss is often suggestive of the deletion or loss of function of tumor suppressor genes. The candidate tumor suppressor genes from these regions are, respectively, MCC and/or APC, p53, and DCC. In order to further our understanding of the molecular and genetic mechanisms involved in tumor progression and, thereby, of normal cell growth, it is important to determine whether defects in one or more of these loci contribute functionally in the progression to malignancy in colorectal cancer and whether correction of any of these defects restores normal growth control in vitro and in vivo. To address this question, we have utilized the technique of microcell-mediated chromosome transfer to introduce normal human chromosomes 5, 17, and 18 individually into recipient colorectal cancer cells. Additionally, chromosome 15 was introduced into SW480 cells as an irrelevant control chromosome. While the introduction of chromosome 17 into the tumorigenic colorectal cell line SW480 yielded no viable clones, cell lines were established after the introduction of chromosomes 15, 5, and 18. Hybrids containing chromosome 18 are morphologically similar to the parental line, whereas those containing chromosome 5 are morphologically distinct from the parental cell line, being small, polygonal, and tightly packed. SW480-chromosome 5 hybrids are strongly suppressed for tumorigenicity, while SW480-chromosome 18 hybrids produce slowly growing tumors in some of the animals injected. Hybrids containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer ot chromosome 18 restored responsiveness to some degree. Our findings indicate that while multiple defects in tumor suppressor genes seem to be required for progression to the malignant state in colorectal cancer, correction of only a single defect can have significant effects in vivo and/or in vitro.

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