Implication of Telomerase in Functions Besides Telomere Elongation in Human Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-40-SCI-40
Author(s):  
Francesca Gazzaniga ◽  
Jue Lin ◽  
Elizabeth Blackburn
Keyword(s):  
Cell Proliferation ◽  
Cancer Cells ◽  
Core Protein ◽  
Human Cells ◽  
Telomere Maintenance ◽  
Telomere Shortening ◽  
Telomere Attrition ◽  
Independent Functions ◽  
Equity Ownership

Abstract Abstract SCI-40 The ribonucleoprotein enzyme telomerase, which counteracts telomere shortening by adding telomeric DNA repeats to the 3’ ends of chromosomes, contains a core protein reverse transcriptase (called hTERT in humans), the essential template-containing RNA (hTER) and associated factors. Thus, telomerase is capable of circumventing the limit on cell division imposed by telomere attrition. Telomerase enzymatic activity is readily detectable in stem and progenitor cell populations, but is largely downregulated in most adult somatic human cells. In contrast, telomerase is highly active in the large majority (∼80%–90%) of cancer cells. While telomerase is essential for telomere maintenance in cells in vitro and in vivo, several studies now also indicate that telomerase may have telomere-independent functions. We previously showed that lowering the level of the telomerase ribonucleoprotein (RNP) enzyme complex causes rapid changes in cell cycle program in human and mouse cancer cells: partial reduction of telomerase induced by directly lowering telomerase RNP component levels causes altered transcriptional profiles and reduced glucose metabolism in human cancer cells, yet bulk telomere shortening or detectable telomere uncapping are not required for these effects. Work by others has shown that reduction of telomerase core protein component level reduced Wnt signaling and caused Wnt-mutant like developmental defects in Xenopus and mouse and aberrant hematopoiesis in zebrafish embryos. We acutely depleted telomerase RNA components in cultured T cells from healthy human adults using shRNAs targeting both the telomerase protein and the RNA component of telomerase (hTR), delivered immediately after in vitro stimulation. Cell proliferation and telomerase activity levels were quantified through the first and second stimulation cycles. Effects of such telomerase RNP reduction on cell proliferation were observed in time frames too short to be accounted for by bulk telomere attrition. Models to account for these findings will be discussed. Disclosures: Lin: Telome Health, Inc.: Consultancy, Equity Ownership. Blackburn:Telome Health, Inc: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism

Science ◽  
2017 ◽  
Vol 357 (6358) ◽  
pp. 1416-1420 ◽  
Author(s):  
Kunitoshi Chiba ◽  
Franziska K. Lorbeer ◽  
A. Hunter Shain ◽  
David T. McSwiggen ◽  
Eva Schruf ◽  
...  
Keyword(s):  
Genome Instability ◽  
Telomere Maintenance ◽  
Second Phase ◽  
Telomere Shortening ◽  
Telomere Attrition ◽  
Cellular Life ◽  
Two Phases ◽  
Promoter Mutations ◽  
Step Mechanism

TERT promoter mutations (TPMs) are the most common noncoding mutations in cancer. The timing and consequences of TPMs have not been fully established. Here, we show that TPMs acquired at the transition from benign nevus to malignant melanoma do not support telomere maintenance. In vitro experiments revealed that TPMs do not prevent telomere attrition, resulting in cells with critically short and unprotected telomeres. Immortalization by TPMs requires a gradual up-regulation of telomerase, coinciding with telomere fusions. These data suggest that TPMs contribute to tumorigenesis by promoting immortalization and genomic instability in two phases. In an initial phase, TPMs do not prevent bulk telomere shortening but extend cellular life span by healing the shortest telomeres. In the second phase, the critically short telomeres lead to genome instability and telomerase is further up-regulated to sustain cell proliferation.

scholarly journals LncRNA UCA1 promotes development of gastric cancer via the miR-145/MYO6 axis

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
An Yang ◽  
Xin Liu ◽  
Ping Liu ◽  
Yunzhang Feng ◽  
Hongbo Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cell Apoptosis ◽  
Gastric Cancer Cell ◽  
Gastric Cancer Cells ◽  
Gastric Cancer Cell Lines ◽  
Development Of Gastric Cancer

Abstract Background Long noncoding RNA (lncRNA), urothelial carcinoma-associated 1 (UCA1) is aberrantly expressed in multiple cancers and has been verified as an oncogene. However, the underlying mechanism of UCA1 in the development of gastric cancer is not fully understood. In the present study, we aimed to identify how UCA1 promotes gastric cancer development. Methods The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data were used to analyze UCA1 and myosin VI (MYO6) expression in gastric cancer. Western blot and quantitative real-time PCR (QPCR) were performed to test the expression level of the UCA1/miR-145/MYO6 axis in gastric cancer cell lines and tissues. The roles of the UCA1/miR-145/MYO6 axis in gastric cancer in vitro and in vivo were investigated by CCK-8 assay, flow cytometry, siRNAs, immunohistochemistry, and a mouse xenograft model. The targeted relationship among UCA1, miR-145, and MYO6 was predicted using LncBase Predicted v.2 and TargetScan online software, and then verified by luciferase activity assay and RNA immunoprecipitation. Results UCA1 expression was higher but miR-145 expression was lower in gastric cancer cell lines or tissues, compared to the adjacent normal cell line or normal tissues. Function analysis verified that UCA1 promoted cell proliferation and inhibited cell apoptosis in the gastric cancer cells in vitro and in vivo. Mechanistically, UCA1 could bind directly to miR-145, and MYO6 was found to be a downstream target gene of miR-145. miR-145 mimics or MYO6 siRNAs could partly reverse the effect of UCA1 on gastric cancer cells. Conclusions UCA1 accelerated cell proliferation and inhibited cell apoptosis through sponging miR-145 to upregulate MYO6 expression in gastric cancer, indicating that the UCA1/miR-145/MYO6 axis may serve as a potential therapeutic target for gastric cancer.

Knockdown CYP2S1 inhibits lung cancer cells proliferation and migration

2021 ◽  
pp. 1-9
Author(s):  
Huan Guo ◽  
Baozhen Zeng ◽  
Liqiong Wang ◽  
Chunlei Ge ◽  
Xianglin Zuo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Lung Cancer Cells ◽  
Invasion And Migration ◽  
And Migration

BACKGROUND: The incidence of lung cancer in Yunnan area ranks firstly in the world and underlying molecular mechanisms of lung cancer in Yunnan region are still unclear. We screened a novel potential oncogene CYP2S1 used mRNA microassay and bioinformation database. The function of CYP2S1 in lung cancer has not been reported. OBJECTIVE: To investigate the functions of CYP2S1 in lung cancer. METHODS: Immunohistochemistry and Real-time PCR were used to verify the expression of CYP2S1. Colony formation and Transwell assays were used to determine cell proliferation, invasion and migration. Xenograft assays were used to detected cell growth in vivo. RESULTS: CYP2S1 is significantly up-regulated in lung cancer tissues and cells. Knockdown CYP2S1 in lung cancer cells resulted in decrease cell proliferation, invasion and migration in vitro. Animal experiments showed downregulation of CYP2S1 inhibited lung cancer cell growth in vivo. GSEA analysis suggested that CYP2S1 played functions by regulating E2F targets and G2M checkpoint pathway which involved in cell cycle. Kaplan-Meier analysis indicated that patients with high CYP2S1 had markedly shorter event overall survival (OS) time. CONCLUSIONS: Our data demonstrate that CYP2S1 exerts tumor suppressor function in lung cancer. The high expression of CYP2S1 is an unfavorable prognostic marker for patient survival.

scholarly journals Inhibition of MCF-7 breast cancer cell proliferation by 5alpha-dihydrotestosterone; a role for p21(Cip1/Waf1)

2004 ◽  
Vol 32 (3) ◽  
pp. 793-810 ◽  
Author(s):  
MA Greeve ◽  
RK Allan ◽  
JM Harvey ◽  
JM Bentel
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
S Phase ◽  
Cyclin D3 ◽  
P27 Kip1 ◽  
Mcf 7

Androgens inhibit the growth of breast cancer cells in vitro and in vivo by mechanisms that remain poorly defined. In this study, treatment of asynchronously growing MCF-7 breast cancer cells with the androgen, 5alpha-dihydrotestosterone (DHT), was shown to inhibit cell proliferation and induce moderate increases in the proportion of G1 phase cells. Consistent with targeting the G1-S phase transition, DHT pretreatment of MCF-7 cultures impeded the serum-induced progression of G1-arrested cells into S phase and reduced the kinase activities of cyclin-dependent kinase (Cdk)4 and Cdk2 to less than 50% of controls within 3 days. DHT treatment was associated with greater than twofold increases in the levels of the Cdk inhibitor, p27(Kip1), while p21(Cip1/Waf1) protein levels remained unchanged. During the first 24 h of DHT treatment, levels of Cdk4-associated p21(Cip1/Waf1) and p27(Kip1) were reduced coinciding with decreased levels of Cdk4-associated cyclin D3. In contrast, DHT treatment caused increased accumulation of Cdk2-associated p21(Cip1/Waf1), with no significant alterations in levels of p27(Kip1) bound to Cdk2 complexes. These findings suggest that DHT reverses the Cdk4-mediated titration of p21(Cip1/Waf1) and p27(Kip1) away from Cdk2 complexes, and that the increased association of p21(Cip1/Waf1) with Cdk2 complexes in part mediates the androgen-induced growth inhibition of breast cancer cells.

scholarly journals Human Endogenous Retrovirus (HERV)-K env Gene Knockout Affects Tumorigenic Characteristics of nupr1 Gene in DLD-1 Colorectal Cancer Cells

2021 ◽  
Vol 22 (8) ◽  
pp. 3941
Author(s):  
Eun-Ji Ko ◽  
Mee-Sun Ock ◽  
Yung-Hyun Choi ◽  
Juan L. Iovanna ◽  
Seyoung Mun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Gene Knockout ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Ros Generation ◽  
Nude Mouse Model ◽  
Env Protein

Human endogenous retroviruses (HERVs) are suggested to be involved in the development of certain diseases, especially cancers. To elucidate the function of HERV-K Env protein in cancers, an HERV-K env gene knockout (KO) in DLD-1 colorectal cancer cell lines was generated using the CRISPR-Cas9 system. Transcriptome analysis of HERV-K env KO cells using next-generation sequencing (NGS) was performed to identify the key genes associated with the function of HERV-K Env protein. The proliferation of HERV-K env KO cells was significantly reduced in in vitro culture as well as in in vivo nude mouse model. Tumorigenic characteristics, including migration, invasion, and tumor colonization, were also significantly reduced in HERV-K env KO cells. Whereas, they were enhanced in HERV-K env over-expressing DLD-1 cells. The expression of nuclear protein-1 (NUPR1), an ER-stress response factor that plays an important role in cell proliferation, migration, and reactive oxygen species (ROS) generation in cancer cells, significantly reduced in HERV-K env KO cells. ROS levels and ROS-related gene expression was also significantly reduced in HERV-K env KO cells. Cells transfected with NUPR1 siRNA (small interfering RNA) exhibited the same phenotype as HERV-K env KO cells. These results suggest that the HERV-K env gene affects tumorigenic characteristics, including cell proliferation, migration, and tumor colonization through NUPR1 related pathway.

The Potential Oncogenic and MLN4924-Resistant Effects of CSN5 on Cervical Cancer Cells

2021 ◽  
Author(s):  
Huilin Zhang ◽  
Ping He ◽  
Qing Zhou ◽  
Yan Lu ◽  
Bingjian Lu
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cervical Cancer Cell ◽  
Cervical Cancers ◽  
Cervical Cancer Cells

Abstract BackgroundsCSN5, a member of Cop9 signalosome, is essential for protein neddylation. It has been supposed to serve as an oncogene in some cancers. However, the role of CSN5 has not been investigated in cervical cancer yet.MethodsData from TCGA cohorts and GEO dataset was analyzed to examine the expression profile of CSN5 in cervical cancers. The role of CSN5 on cervical cancer cell proliferation was investigated in cervical cancer cell lines, Siha and Hela, through CSN5 knockdown via CRISPR-CAS9. Western blot was used to detect the effect of CSN5 knockdown and overexpression. CCK8, clone formation assay and cell cycle assay were also employed. Besides, the role CSN5 knockdown in vivo was evaluated by xenograft tumor model. Moreover, MLN4924 was applied in Siha and Hela with CSN5 overexpression.ResultsWe found that downregulation of CSN5 in Siha and Hela cells inhibited cell proliferation in vitro and in vivo, and the inhibitory effects were largely rescued by CSN5 overexpression. Moreover, deletion of CSN5 caused cell cycle arrest rather than inducing apoptosis. Importantly, CSN5 overexpression confers resistance to the anti-cancer effects of MLN4924 (pevonedistat) in cervical cancer cells.ConclusionsOur findings demonstrated that CSN5 functions as an oncogene in cervical cancers and may serve as a potential indicator for predicting the effects of MLN4924 treatment in the future.

scholarly journals Telomere length and human hippocampal neurogenesis

2020 ◽  
Vol 45 (13) ◽  
pp. 2239-2247 ◽  
Author(s):  
Alish B. Palmos ◽  
Rodrigo R. R. Duarte ◽  
Demelza M. Smeeth ◽  
Erin C. Hedges ◽  
Douglas F. Nixon ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Psychiatric Disorder ◽  
Telomere Length ◽  
Gene Networks ◽  
Hippocampal Neurogenesis ◽  
Telomere Maintenance ◽  
Adult Hippocampal Neurogenesis ◽  
Telomere Shortening ◽  
Age Related

Abstract Short telomere length is a risk factor for age-related disease, but it is also associated with reduced hippocampal volumes, age-related cognitive decline and psychiatric disorder risk. The current study explored whether telomere shortening might have an influence on cognitive function and psychiatric disorder pathophysiology, via its hypothesised effects on adult hippocampal neurogenesis. We modelled telomere shortening in human hippocampal progenitor cells in vitro using a serial passaging protocol that mimics the end-replication problem. Serially passaged progenitors demonstrated shorter telomeres (P ≤ 0.05), and reduced rates of cell proliferation (P ≤ 0.001), with no changes in the ability of cells to differentiate into neurons or glia. RNA-sequencing and gene-set enrichment analyses revealed an effect of cell ageing on gene networks related to neurogenesis, telomere maintenance, cell senescence and cytokine production. Downregulated transcripts in our model showed a significant overlap with genes regulating cognitive function (P ≤ 1 × 10−5), and risk for schizophrenia (P ≤ 1 × 10−10) and bipolar disorder (P ≤ 0.005). Collectively, our results suggest that telomere shortening could represent a mechanism that moderates the proliferative capacity of human hippocampal progenitors, which may subsequently impact on human cognitive function and psychiatric disorder pathophysiology.

scholarly journals Demethoxycurcumin inhibited human epithelia ovarian cancer cells’ growth via up-regulating miR-551a

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769430 ◽  
Author(s):  
Zhenhua Du ◽  
Xianqun Sha
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Natural Form ◽  
Ovarian Cancer Cell Lines ◽  
Induced Apoptosis ◽  
Tumor Suppressive Function ◽  
Cancer Tissues

Curcumin is a natural agent that has ability to dampen tumor cells’ growth. However, the natural form of curcumin is prone to degrade and unstable in vitro. Here, we demonstrated that demethoxycurcumin (a curcumin-related demethoxy compound) could inhibit cell proliferation and induce apoptosis of ovarian cancer cells. Moreover, IRS2/PI3K/Akt axis was inactivated in cells treated with demethoxycurcumin. Quantitative real-time reverse transcription polymerase chain reaction demonstrated that miR-551a was down-regulated in ovarian cancer tissues and ovarian cancer cell lines. Over-expression of miR-551a inhibited cell proliferation and induced apoptosis of ovarian cancer cells, whereas down-regulation of miR-551a exerted the opposite function. Luciferase assays confirmed that there was a binding site of miR-551a in IRS2, and we found that miR-551a exerted tumor-suppressive function by targeting IRS2 in ovarian cancer cells. Remarkably, miR-551a was up-regulated in the cells treated with demethoxycurcumin, and demethoxycurcumin suppressed IRS2 by restoration of miR-551a. In conclusion, demethoxycurcumin hindered ovarian cancer cells’ malignant progress via up-regulating miR-551a.

scholarly journals Omega-3 Fatty Acids and PPARγin Cancer

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-14 ◽  
Author(s):  
Iris J. Edwards ◽  
Joseph T. O'Flaherty
Keyword(s):  
Fatty Acids ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Dietary Fatty Acids ◽  
Human Populations ◽  
Peroxisome Proliferator ◽  
Omega 3 ◽  
New Paradigm

Omega-3 (or n-3) polyunsaturated fatty acids (PUFAs) and their metabolites are natural ligands for peroxisome proliferator receptor activator (PPAR)γand, due to the effects of PPARγon cell proliferation, survival, and differentiation, are potential anticancer agents. Dietary intake of omega-3 PUFAs has been associated with a reduced risk of certain cancers in human populations and in animal models. In vitro studies have shown that omega-3 PUFAs inhibit cell proliferation and induce apoptosis in cancer cells through various pathways but one of which involves PPARγactivation. The differential activation of PPARγand PPARγ-regulated genes by specific dietary fatty acids may be central to their distinct roles in cancer. This review summarizes studies relating PUFAs to PPARγand cancer and offers a new paradigm relating an n-3 PUFA through PPARγto the expression of the cell surface proteoglycan, syndecan-1, and to the death of cancer cells.

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