scholarly journals miR-378d Regulates Polyploidization and Malignant Phenotype of Tumor Cells Through AKT and RhoA

2021 ◽  
Author(s):  
Wei Wang ◽  
Jie Peng ◽  
Susu Shi ◽  
Juan Yu ◽  
Jianli Liu ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Good Prognosis ◽  
Biological Behavior ◽  
Beta Catenin ◽  
Malignant Phenotype ◽  
Esophageal Squamous Cell Carcinomas ◽  
Related Proteins ◽  
The Impact

Studies have shown that stress such as hypoxia, chemotherapy, radiotherapy can lead to polyploidization of tumor cells, which play an important role in tumor heterogeneity and malignant phenotype. Paclitaxel (PTX) treatment promoted polyploid cancer cells (PCCs) formation, and miR-378d is sharply reduced in PCCs of esophageal squamous cell carcinomas (ESCC) cells, but miR-378d participation PCCs formation and the impact on the biological behavior of ESCC remains unclear. We analyzed the PCCs formation and biological behavior of ESCC cells in vivo and in vitro, and the related proteins regulated by miR-378d. Results showed that miR-378d expression was associated with good prognosis in ESCC patients. miR-378d inhibition promoted PCCs formation, heterogenicity, chemo-resistance, monoclonal formation, EMT, migration, invasion, stemness and metastasis of ESCC cells. miR-378d can target downregulated AKT1, and inactivating the AKT-β-catenin signaling pathway, miR-378d and AKT can also regulated RhoA expression. AKT and RhoA regulated polyploidization and depolyploidization. Therefore, miR-378d expression is a good prognostic factor of ESCC patients and regulates polyploidization and malignant phenotype of tumor cells through AKT and RhoA.

scholarly journals Combinations of TLR Ligands: A Promising Approach in Cancer Immunotherapy

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Saskia Stier ◽  
Claudia Maletzki ◽  
Ulrike Klier ◽  
Michael Linnebacher
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Cell Lines ◽  
Immune Cells ◽  
Human Lymphocytes ◽  
Growth Control ◽  
Poly I:C ◽  
The Impact

Toll-like receptors (TLRs), a family of pattern recognition receptors recognizing molecules expressed by pathogens, are typically expressed by immune cells. However, several recent studies revealed functional TLR expression also on tumor cells. Their expression is a two-sided coin for tumor cells. Not only tumor-promoting effects of TLR ligands are described but also direct oncopathic and immunostimulatory effects. To clarify TLRs’ role in colorectal cancer (CRC), we tested the impact of the TLR ligands LPS, Poly I:C, R848, and Taxol on primary human CRC cell lines (HROC40, HROC60, and HROC69)in vitroandin vivo(CT26). Taxol, not only a potent tumor-apoptosis-inducing, but also TLR4-activating chemotherapeutic compound, inhibited growth and viability of all cell lines, whereas the remaining TLR ligands had only marginal effects (R848 > LPS > Poly I:C). Combinations of the substances here did not improve the results, whereas antitumoral effects were dramatically boosted when human lymphocytes were added. Here, combining the TLR ligands often diminished antitumoral effects.In vivo, best tumor growth control was achieved by the combination of Taxol and R848. However, when combined with LPS, Taxol accelerated tumor growth. These data generally prove the potential of TLR ligands to control tumor growth and activate immune cells, but they also demonstrate the importance of choosing the right combinations.

scholarly journals Distribution and vulnerability of transcriptional outputs across the genome in Myc-amplified medulloblastoma cells

2021 ◽  
Author(s):  
Rui Yang ◽  
Wenzhe Wang ◽  
Meichen Dong ◽  
Kristen Roso ◽  
Paula Greer ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Target Genes ◽  
De Novo ◽  
Inhibitory Effect ◽  
Nucleotide Synthesis ◽  
High Level ◽  
The Impact

Myc plays a central role in tumorigenesis by orchestrating the expression of genes essential to numerous cellular processes1-4. While it is well established that Myc functions by binding to its target genes to regulate their transcription5, the distribution of the transcriptional output across the human genome in Myc-amplified cancer cells, and the susceptibility of such transcriptional outputs to therapeutic interferences remain to be fully elucidated. Here, we analyze the distribution of transcriptional outputs in Myc-amplified medulloblastoma (MB) cells by profiling nascent total RNAs within a temporal context. This profiling reveals that a major portion of transcriptional action in these cells was directed at the genes fundamental to cellular infrastructure, including rRNAs and particularly those in the mitochondrial genome (mtDNA). Notably, even when Myc protein was depleted by as much as 80%, the impact on transcriptional outputs across the genome was limited, with notable reduction mostly only in genes involved in ribosomal biosynthesis, genes residing in mtDNA or encoding mitochondria-localized proteins, and those encoding histones. In contrast to the limited direct impact of Myc depletion, we found that the global transcriptional outputs were highly dependent on the activity of Inosine Monophosphate Dehydrogenases (IMPDHs), rate limiting enzymes for de novo guanine nucleotide synthesis and whose expression in tumor cells was positively correlated with Myc expression. Blockage of IMPDHs attenuated the global transcriptional outputs with a particularly strong inhibitory effect on infrastructure genes, which was accompanied by the abrogation of MB cells proliferation in vitro and in vivo. Together, our findings reveal a real time action of Myc as a transcriptional factor in tumor cells, provide new insight into the pathogenic mechanism underlying Myc-driven tumorigenesis, and support IMPDHs as a therapeutic vulnerability in cancer cells empowered by a high level of Myc oncoprotein.

Effect of hyperthermia on the viability and proliferative activity of tumor cells

2016 ◽  
Vol 21 (5) ◽  
pp. 250-252
Author(s):  
N. Yu Anisimova ◽  
M. V Kiselevskiy ◽  
Amir G. Abdullaev ◽  
N. V Malakhova ◽  
S. M Sitdikova ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Physiological Activity ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Transformed Cells ◽  
Cell Mortality ◽  
Temperature Exposure ◽  
The Impact

Introduction. Results of the systemic chemotherapy in the peritoneum canceromatosis are unsatisfactory because of poor penetration of anticancer drugs in serous cavities due to the presence ofperitoneal-plasma barrier. One of the possible ways to enhance the action cytostatic agents is the use of chemotherapy and hyperthermia, which, according to some data, has an own cytotoxic effect. The purpose of the study. The study of the effect ofdifferent modes of hyperthermia on the physiological activity of transplantable lines of tumor and non-transformed cells. Results. Analysis of the impact of hyperthermia on the physiological activity of transplantable lines of tumor and the non-transformed cells in vitro and in vivo studies demonstrated that along with the gain in the level and time of the temperature exposure as the degree of damage as tumor cell mortality rate increases. In this study the most effective treatment was as follows: the temperature is above 45°C with the exposure of more than 2 hours, which is difficult to achieve in practice due to the limited tolerance of healthy tissues. Conclusion. With the use of hyperthermia in monoregimen it is not possible to achieve effective levels of the temperature impact, which could hardly have a significant inhibitory effect on tumor cells.

scholarly journals B4GalT1 Regulates Apoptosis and Autophagy of Glioblastoma In Vitro and In Vivo

2020 ◽  
Vol 19 ◽  
pp. 153303382098010
Author(s):  
Pu Wang ◽  
Xiaolong Li ◽  
Yuan Xie
Keyword(s):  
Tumor Cells ◽  
Mrna Level ◽  
Downstream Target ◽  
New Strategy ◽  
Gene Correlation ◽  
Variable Gene ◽  
Development In Vitro ◽  
Related Proteins

Our study was designed to investigate the role of B4GalT1 in glioblastoma, in vitro and in vivo, to detect whether B4GalT1 knockdown could regulate the development of glioblastoma, and further observe the relationship between B4GalT1 knockdown and the apoptosis and autophagy of glioblastoma. To begin, we looked at TCGA and GEPIA systems to predict the potential function of B4GalT1. Western blot and RT-PCR were used to analyze the expression, or mRNA level, of B4GalT1 at different tissue or cell lines. Next, the occurrence and development of glioblastoma, in vitro and in vivo, was observed by using B4GalT1 knocked down by lentivirus. Finally, the apoptosis and autophagy of glioblastoma was observed in vitro and in vivo. Results show that B4GalT1 was a highly variable gene, and GEPIA and TCGA systems show B4GalT1 expression in GBM tumor tissue was higher than in normal tissue. Pair-wise gene correlation analysis revealed a probable relationship between B4GalT1 and autophagy related proteins. The B4GalT1 expression and mRNA level were increased in tumor cells, or U87 cells. B4GalT1 knocked down by lentivirus could inhibit glioblastoma development, in vitro and in vivo, by reducing tumor weight and volume, increasing survival, and weakening tumor cells proliferation, migration, invasion. B4GalT1 knockdown could increase apoptosis and autophagy of glioblastoma in vitro and in vivo. Our study demonstrates that B4GalT1 may be able to regulate apoptosis and autophagy of glioblastoma. Bax, Bcl-2, cleaved caspase-3, Beclin-1, and LC3 s may be the downstream target factors of B4GalT1 in apoptosis and autophagy, which may provide a new strategy to reduce glioblastoma development by regulating apoptosis and autophagy.

scholarly journals BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i5-i5
Author(s):  
Rui Yang ◽  
Wenzhe Wang ◽  
Meichen Dong ◽  
Kristen Roso ◽  
Xuhui Bao ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Target Genes ◽  
De Novo ◽  
Inhibitory Effect ◽  
Nucleotide Synthesis ◽  
Expression Of Genes ◽  
High Level ◽  
The Impact

Abstract Myc plays a central role in tumorigenesis by orchestrating the expression of genes essential to numerous cellular processes. While it is well established that Myc functions by binding to its target genes to regulate their transcription, the distribution of the transcriptional output across human genome in Myc-amplified cancer cells, and the susceptibility of such transcriptional outputs to therapeutic interferences remain to be fully elucidated. Here, we analyze the distribution of transcriptional outputs in Myc-amplified medulloblastoma (MB) cells by profiling nascent total RNAs within a temporal context. This profiling reveals a major portion of transcriptional action in these cells was directed at the genes fundamental to cellular infrastructures, including rRNAs and particularly those in the mitochondrial genome (mtDNA). Notably, even when Myc protein was depleted by as much as 80%, the impact on transcriptional outputs across the genome was limited, with notable reduction mostly in genes of involved in ribosomal biosynthesis, genes residing in mtDNA or encoding mitochondria-localized proteins, and those encoding histones. In contrast to the limited direct impact of Myc depletion, we found that the global transcriptional outputs were highly dependent on the activity of Inosine Monophosphate Dehydrogenases (IMPDHs), rate limiting enzymes for de novo guanine nucleotide synthesis and whose expression in tumor cells was positively correlated with Myc’s expression. Blockage of IMPDHs attenuated the global transcriptional outputs with a particularly strong inhibitory effect on the aforementioned infrastructure genes, which was accompanied by the abrogation of MB cell’s proliferation in vitro and in vivo. Together, our findings reveal a real time action of Myc as a transcriptional factor in tumor cells, gain new insight into the pathogenic mechanism underlying Myc-driven tumorigenesis, and support IMPDHs as a therapeutic vulnerability in MB cells empowered by a high level of Myc oncoprotein.

The In Vivo Impact of Human Regulatory T Cells on the Graft Versus Tumor Effect.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 349-349 ◽  
Author(s):  
Tuna Mutis ◽  
Henk Rozemuller ◽  
Maarten E. Emmelot ◽  
Tineke Aarts-Riemens ◽  
Vivienne Verweij ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Tumor Cells ◽  
Cell Reactivity ◽  
Human Pbmc ◽  
Ifn Γ ◽  
T Cell Reactivity ◽  
The Impact

Abstract The curative Graft-vs-Tumor effect (GvT) of allogeneic Stem cell transplantation (SCT) is frequently complicated with life threatening Graft-vs-Host Disease (GvHD). In mice, prevention of GvHD, without abrogation of GvT is possible by co-transplantation of naturally occurring regulatory T cells (Tregs) with SC grafts. Consistent with these murine studies, we recently demonstrated that also human Tregs possess potent GvHD-downregulatory capacities in a xenogeneic(x) model, where x-GvHD is induced by infusion of autologous human T cells in RAG2−/−γc−/− mice (Mutis et al. Clin. Cancer Res.2006, 12: 5520–5525). Towards clinical application of Tregs, we now explored the impact of human Treg-administration on GvT in a bioluminescence imaging (BLI) based human-GvT model in the RAG2−/−γc−/− mice. In this model, mice inoculated with luciferase (LUC)-transduced human myeloma (MM) cell lines developed BLI-detectable, progressive, MM-like multifocal tumors exclusively in the bone marrow (BM). Full blown tumors were effectively eliminated by infusion of allogeneic human PBMC. This treatment also caused lethal x-GvHD as expected. In this setting, co-infusion of human PBMC with autologous, in vitro cultured Tregs at a 1:1 Treg: T effector cell ratio had no adverse effects on the development of GvT while significantly reducing the lethality of x-GvHD. In vitro analyses of sacrificed mice at day 21 revealed that administered Tregs homed to BM and spleen, significantly downregulated the total numbers of IFN-γ-producing CD4+ and CD8+ T cells responding to CD3 mediated signals, but had no downregulatory effect on the frequencies of IFN-γ-producing T cells responding to tumor cells. There was also no downregulation of cytotoxic activity against tumor cells in Treg-treated mice. Conclusively, these results showed that Tregs, at doses which are inhibitory for x-GvHD-inducing T cells, could maintain the GvT effect by allowing T cell reactivity against tumor cells. Human Tregs thus still hold promise as attractive cellular tools for separating GvT from GvHD.

scholarly journals In Vitro Glioblastoma Models: A Journey into the Third Dimension

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2449
Author(s):  
Mayra Paolillo ◽  
Sergio Comincini ◽  
Sergio Schinelli
Keyword(s):  
Tumor Cells ◽  
Single Cell Analysis ◽  
3D Models ◽  
Primary Brain Tumor ◽  
Molecular Features ◽  
Third Dimension ◽  
One Year ◽  
The Impact

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults, with an average survival time of about one year from initial diagnosis. In the attempt to overcome the complexity and drawbacks associated with in vivo GBM models, together with the need of developing systems dedicated to screen new potential drugs, considerable efforts have been devoted to the implementation of reliable and affordable in vitro GBM models. Recent findings on GBM molecular features, revealing a high heterogeneity between GBM cells and also between other non-tumor cells belonging to the tumoral niche, have stressed the limitations of the classical 2D cell culture systems. Recently, several novel and innovative 3D cell cultures models for GBM have been proposed and implemented. In this review, we first describe the different populations and their functional role of GBM and niche non-tumor cells that could be used in 3D models. An overview of the current available 3D in vitro systems for modeling GBM, together with their major weaknesses and strengths, is presented. Lastly, we discuss the impact of groundbreaking technologies, such as bioprinting and multi-omics single cell analysis, on the future implementation of 3D in vitro GBM models.

scholarly journals Spontaneous Cell Fusions as a Mechanism of Parasexual Recombination in Tumor Cell Populations

2020 ◽  
Author(s):  
Daria Miroshnychenko ◽  
Etienne Baratchart ◽  
Meghan C. Ferrall-Fairbanks ◽  
Robert Vander Velde ◽  
Mark A Laurie ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Adaptive Landscape ◽  
Cell Populations ◽  
Phenotypic Traits ◽  
Multiple Sources ◽  
Somatic Evolution ◽  
The Impact ◽  
Cell Fusions

ABSTRACTInitiation and progression of cancers reflect the underlying process of somatic evolution, which follows a Darwinian logic, i.e., diversification of heritable phenotypes provides a substrate for natural selection, resulting in the outgrowth of the most fit subpopulations. Although somatic evolution can tap into multiple sources of diversification, it is assumed to lack access to (para)sexual recombination – a key diversification mechanism throughout all strata of life. Based on observations of spontaneous fusions involving cancer cells, reported genetic instability of polypoid cells, and precedence of fusion-mediated parasexual recombination in fungi, we asked whether cell fusions could serve as a source of parasexual recombination in cancer cell populations. Using differentially labelled tumor cells, we found evidence of low-frequency, spontaneous cell fusions between carcinoma cells in multiple cell line models of breast cancer both in vitro and in vivo. While some hybrids remained polyploid, many displayed partial ploidy reduction, generating diverse progeny with heterogeneous inheritance of parental alleles, indicative of partial recombination. Hybrid cells also displayed elevated levels of phenotypic plasticity, which may further amplify the impact of cell fusions on the diversification of phenotypic traits. Using mathematical modeling, we demonstrated that the observed rates of spontaneous somatic cell fusions may enable populations of tumor cells to amplify clonal heterogeneity, thus facilitating the exploration of larger areas of the adaptive landscape, relative to strictly asexual populations, which may substantially accelerate a tumor’s ability to adapt to new selective pressures.

Silencing of MED27 inhibits adrenal cortical carcinogenesis by targeting the Wnt/β-catenin signaling pathway and the epithelial-mesenchymal transition process

2018 ◽  
Vol 399 (6) ◽  
pp. 593-602 ◽  
Author(s):  
Hongchao He ◽  
Jun Dai ◽  
Xiaoqun Yang ◽  
Xiaojing Wang ◽  
Fukang Sun ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Transition Process ◽  
Tumor Xenograft ◽  
Mesenchymal Transition ◽  
Related Proteins ◽  
The Impact

AbstractThis study aimed to explore the effect ofMED27on the expression of epithelial-mesenchymal transition (EMT)-related proteins and β-catenin in adrenal cortical carcinoma (ACC). The functional mechanism ofMED27on ACC processes was also explored. The expression ofMED27was assessed by quantitative real-time polymerase chain reaction (qRT-PCR). siRNA was utilized to knockdown the expression ofMED27. CCK8 assays were performed to evaluate SW-13 cell proliferation. Transwell assays were performed to assess the invasion ability, and wound healing assays were utilized to detect migration. A tumor xenograft mouse model was established to investigate the impact of silencingMED27on tumor growth and metastasis.MED27was highly expressed in ACC tissues and cells. Down-regulation ofMED27induced ACC cell apoptosis, and significantly attenuated ACC cell proliferation, invasion and metastasisin vivoandin vitro.MED27knockdown regulated the expression of EMT-related proteins and Wnt/β-catenin signaling pathway-related proteins. Our study investigated the function and mechanism ofMED27and validated thatMED27plays a negative role in ACC occurrence and progression and could be utilized as a new therapeutic target in ACC prevention and treatment.

scholarly journals Transcription factor NFAT5 contributes to the glycolytic phenotype rewiring and pancreatic cancer progression via transcription of PGK1

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Yongsheng Jiang ◽  
Ruizhe He ◽  
Yuhong Jiang ◽  
Dejun Liu ◽  
Lingye Tao ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Phosphoglycerate Kinase ◽  
Underlying Mechanism ◽  
Biological Behavior ◽  
Ductal Adenocarcinoma ◽  
Clinical Samples ◽  
Activated T Cells ◽  
The Impact

AbstractHypoxia and the hypovascular tumor microenvironment are major hallmarks of pancreatic ductal adenocarcinoma (PDAC), in which glycolysis is of great importance to tumor survival and proliferation. There is little research regarding the role of Nuclear Factor of Activated T Cells 5 (NFAT5) in relation to carcinoma. Here, we explored the impact of NFAT5 on the biological behavior of PDAC and the underlying mechanism. We demonstrated that NFAT5 was highly expressed in PDAC and was related to poorer prognosis. Knockdown of NFAT5 lead to impaired proliferation of tumor cells caused by an aberrant Warburg effect. Mechanically, phosphoglycerate kinase 1 (PGK-1), which is the first enzyme generating ATP in glycolysis, was verified as a target gene of NFAT5. Over-expression of PGK1 compromised the aberrant oncological behavior caused by knockdown of NFAT5 both in vitro and in vivo. Clinical samples underwent positron emission tomography-computed tomography (PET-CT) examination and KrasG12D/+/Trp53R172H/+/Pdx1-Cre (KPC) mice were collected to support our conclusion.

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