scholarly journals Analysis of miRNA-mRNA Crosstalk in Radiation-Induced Mouse Thymic Lymphomas to Identify miR-486 as a Critical Regulator by Targeting IGF2BP3 mRNA

2021 ◽  
Vol 10 ◽  
Author(s):  
Hainan Zhao ◽  
Suhe Dong ◽  
Jicong Du ◽  
Penglin Xia ◽  
Ruling Liu ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Target Genes ◽  
Environmental Carcinogens ◽  
Mice Model ◽  
Lymphoma Cells ◽  
Over Expression ◽  
Mirna Array ◽  
Radiation Induced ◽  
The Relationship

Ionizing radiation is one of the common environmental carcinogens. miRNAs play critical roles in the processes of tumor occurrence, development, metastasis. However, the relationship between radiation-induced carcinogenesis and miRNA rarely reported. This study is aimed to investigate the effect of miRNAs on radiation-induced carcinogenesis. In this study we established the radiation-induced thymic lymphoma mice model. By using miRNA array of RTL tissue and predicting for miRNAs target genes, a miRNA-mRNA crosstalk network was established. Based on this network, we identified a critical miRNA, miR-486, which was the most down-regulated in the radiation-induced carcinogenesis. Then the function of miR-486 was confirmed by using knockout mice and cellular experiments. As a result, miR-486 could inhibit proliferation of mouse lymphoma cells by targeting IGF2BP3 mRNA. The adenovirus over-expression miR-486 vector reduced tumorigenesis in vivo. MiR-486 knockout mice have a strong tendency of radiation-induced carcinogenesis. In conclusion, miR-486 inhibits the proliferation of lymphoma cells and tumorigenesis induced by radiation through targeting IGF2BP3.

scholarly journals Chondroitin polymerizing factor (CHPF) promotes development of malignant melanoma through regulation of CDK1

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Wei Sun ◽  
Fang Zhao ◽  
Yu Xu ◽  
Kai Huang ◽  
Xianling Guo ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Pathway Analysis ◽  
Normal Skin ◽  
Over Expression ◽  
Tumor Promotor ◽  
And Migration ◽  
First Time ◽  
The Relationship

Abstract Chondroitin polymerizing factor (CHPF) is an important member of glycosyltransferases involved in the biosynthesis of chondroitin sulfate (CS). However, the relationship between CHPF and malignant melanoma (MM) is still unknown. In this study, it was demonstrated that CHPF was up-regulated in MM tissues compared with the adjacent normal skin tissues and its high expression was correlated with more advanced T stage. Further investigations indicated that the over-expression/knockdown of CHPF could promote/inhibit proliferation, colony formation and migration of MM cells, while inhibiting/promoting cell apoptosis. Moreover, knockdown of CHPF could also suppress tumorigenicity of MM cells in vivo. RNA-sequencing followed by Ingenuity pathway analysis (IPA) was performed for exploring downstream of CHPF and identified CDK1 as the potential target. Furthermore, our study revealed that knockdown of CDK1 could inhibit development of MM in vitro, and alleviate the CHPF over-expression induced promotion of MM. In conclusion, our study showed, as the first time, CHPF as a tumor promotor for MM, whose function was carried out probably through the regulation of CDK1.

scholarly journals Maximal killing of lymphoma cells by DNA damage–inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5256-5267 ◽  
Author(s):  
Lina Happo ◽  
Mark S. Cragg ◽  
Belinda Phipson ◽  
Jon M. Haga ◽  
Elisa S. Jansen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Drug Resistance ◽  
Target Genes ◽  
B Cell Lymphoma ◽  
Chemotherapeutic Agents ◽  
Lymphoid Cells ◽  
Lymphoma Cells ◽  
P53 Target Genes

Abstract DNA-damaging chemotherapy is the backbone of cancer treatment, although it is not clear how such treatments kill tumor cells. In nontransformed lymphoid cells, the combined loss of 2 proapoptotic p53 target genes, Puma and Noxa, induces as much resistance to DNA damage as loss of p53 itself. In Eμ-Myc lymphomas, however, lack of both Puma and Noxa resulted in no greater drug resistance than lack of Puma alone. A third B-cell lymphoma-2 homology domain (BH)3-only gene, Bim, although not a direct p53 target, was up-regulated in Eμ-Myc lymphomas incurring DNA damage, and knockdown of Bim levels markedly increased the drug resistance of Eμ-Myc/Puma−/−Noxa−/− lymphomas both in vitro and in vivo. Remarkably, c-MYC–driven lymphoma cell lines from Noxa−/−Puma−/−Bim−/− mice were as resistant as those lacking p53. Thus, the combinatorial action of Puma, Noxa, and Bim is critical for optimal apoptotic responses of lymphoma cells to 2 commonly used DNA-damaging chemotherapeutic agents, identifying Bim as an additional biomarker for treatment outcome in the clinic.

scholarly journals microRNA-155-3p delivered by M2 macrophages-derived exosomes enhances the progression of medulloblastoma through regulation of WDR82

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Li Song ◽  
Bin Luan ◽  
Qingrong Xu ◽  
Ruihe Shi ◽  
Xiufang Wang
Keyword(s):  
Molecular Subtype ◽  
Luciferase Assay ◽  
M2 Macrophages ◽  
Mice Model ◽  
Repeat Domain ◽  
Relationship Of ◽  
Tumor Pathogenesis ◽  
The Relationship

Abstract Objective Exosomes, membranous nanovesicles, naturally bringing proteins, mRNAs, and microRNAs (miRNAs), play crucial roles in tumor pathogenesis. This study was to investigate the role of miR-155-3p from M2 macrophages-derived exosomes (M2-Exo) in promoting medulloblastoma (MB) progression by mediating WD repeat domain 82 (WDR82). Methods miR-155-3p expression was detected by RT-qPCR. The relationship of miR-155-3p with clinicopathological features of MB patients was analyzed. M2-Exo were isolated and identified by TEM, NTA and Western blot. CCK-8 assay, colony formation assay, flow cytometry, wound healing assay, and Transwell assay were performed to explore the role of miR-155-3p-enriched M2-Exo on the progression of MB cells. Luciferase assay were used to identify the relationship between miR-155-3p and WDR82. The effect of miR-155-3p-enriched M2-Exo on tumorigenesis of MB was confirmed by the xenograft nude mice model. Results miR-155-3p was up-regulated in MB tissues of patients and MB cell lines. High miR-155-3p expression was correlated with the pathological type and molecular subtype classification of MB patients. WDR82 was a direct target of miR-155-3p. miR-155-3p was packaged into M2-Exo. miR-155-3p-enriched M2-Exo promoted the progression of Daoy cells. miR-155-3p-enriched M2-Exo promoted in vivo tumorigenesis. Conclusion The study highlights that miR-155-3p-loaded M2-Exo enhances the growth of MB cells via down-regulating WDR82, which might provide a deep insight into MB mechanism.

scholarly journals Radiosensitivity of Cancer Cells Is Regulated by Translationally Controlled Tumor Protein

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 386 ◽  
Author(s):  
Jiwon Jung ◽  
Ji-Sun Lee ◽  
Yun-Sil Lee ◽  
Kyunglim Lee
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
A549 Cells ◽  
Breast Cancer Cell Lines ◽  
Multifunctional Protein ◽  
Translationally Controlled Tumor Protein ◽  
Control Shrna ◽  
Radiation Induced ◽  
The Relationship

Translationally controlled tumor protein (TCTP) is a ubiquitous multifunctional protein that is essential for cell survival. This study reveals that the regulation of radiosensitivity of cancer cells is yet another function of TCTP. The relationship between endogenous TCTP levels and sensitivity to radiation was examined in breast cancer cell lines (T47D, MDA-MB-231, and MCF7) and lung cancer cells lines (A549, H1299, and H460). Cancer cells with high expression levels of TCTP were more resistant to radiation. TCTP overexpression inhibited radiation-induced cell death, while silencing TCTP led to an increase in radiosensitivity. DNA damage in the irradiated TCTP-silenced A549 cells was greater than in irradiated control shRNA-transfected A549 cells. p53, a well-known reciprocal regulator of TCTP, was increased in irradiated TCTP down-regulated A549 cells. Moreover, introduction of p53 siRNA in TCTP knocked-down A549 cells abrogated the increased radiosensitivity induced by TCTP knockdown. An in vivo xenograft study also confirmed enhanced radiosensitivity in TCTP down-regulated A549 cells. These findings suggest that TCTP has the potential to serve as a therapeutic target to overcome radiation resistance in cancer, a major problem for the effective treatment of cancers.

The Deficiency of Maged1 Attenuates Parkinson's Disease Progression by Inhibiting Apoptosis and Enhancing Autophagy in Mice

2020 ◽  
Author(s):  
Jie Wang ◽  
Wei-Yan You ◽  
Qing Ye ◽  
Jia-Qi Zhang ◽  
Chuan He ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Signaling Pathway ◽  
Knockout Mice ◽  
Gene Transfection ◽  
Motor Deficits ◽  
Mice Model

Abstract Background: Melanoma-associated antigen D1 (Maged1) is expressed in most adult tissues, predominantly in the brain, and has critical functions in the central nervous system in both developmental and adult stages. Loss of Maged1 in mice has been linked to depression, cognitive disorder, circadian rhythm, and drug addiction. However, the role of Maged1 in Parkinson’s disease (PD) remains unclear.Methods: Immunostaining was performed to investigate the expression of Maged1 in the samples from mice and human. To make the acute mice model of PD, C57BL/6 mice and Maged1 knockout mice were injected with 20 mg/kg 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) four times, every 2-hour intervals. SY5Y cells were treated by 200 μM 1-Methyl-4-phenylpyridinium iodide (MPP+). To examine motor balance and coordination, the rotarod test and pole test were used. Then we further investigated the role of Maged1 deficiency in DA neurons by high-performance liquid chromatography, immunohistochemistry, western blot, CCK8 assay, and gene transfection in vivo or in vitro.Results: Maged1 was expressed in DA neurons of samples from mice and human. And the expression of Maged1 was time-dependently upregulated by the treatment with MPTP or MPP+ in vivo or in vitro. Knockout of Maged1 in mice partly rescued the motor deficits and the reduced levels of striatal dopamine and its metabolites by MPTP treatment. Moreover, Maged1 deficiency protected primary DA neurons and differentiated ReNcell VM cells from MPP+ toxicity. Furthermore, along with the overexpression or downregulation of Maged1 in cultured SH-SY5Y cells, the reduced the cell viability by MPP+ treatment was relatively aggerated or attenuated. The effect of Maged1 deficiency may be attributed to the upregulated Akt signaling pathway and the downregulated mTOR signaling pathway, which further attenuated the MPTP or MPP+ -induced cell apoptosis and impairment of autophagy. Consistent with the above data, the degeneration of midbrain and striatum among 15-m Maged1 knockout mice was relatively mild compared to those in 15-m wild-type mice under physiological conditions.Conclusions: Maged1 deficiency-mediated apoptosis inhibition and autophagy enhancement may be a potential pro-survival mechanism during the progression of PD.

scholarly journals Redundancy in Tumor Necrosis Factor (TNF) and Lymphotoxin (LT) Signaling In Vivo: Mice with Inactivation of the Entire TNF/LT Locus versus Single-Knockout Mice

2002 ◽  
Vol 22 (24) ◽  
pp. 8626-8634 ◽  
Author(s):  
Dmitry V. Kuprash ◽  
Marat B. Alimzhanov ◽  
Alexei V. Tumanov ◽  
Sergei I. Grivennikov ◽  
Alexander N. Shakhov ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Knockout Mice ◽  
Tumor Necrosis ◽  
Target Genes ◽  
Recombination System ◽  
Major Histocompatibility Complex Locus ◽  
Cell Compartmentalization ◽  
Necrosis Factor ◽  
Single Knockout

ABSTRACT Homologous genes and gene products often have redundant physiological functions. Members of the tumor necrosis factor (TNF) family of cytokines can signal activation, proliferation, differentiation, costimulation, inhibition, or cell death, depending on the type and status of the target cell. TNF, lymphotoxin α (LTα), and LTβ form a subfamily of a larger family of TNF-related ligands with their genes being linked within a compact 12-kb cluster inside the major histocompatibility complex locus. Singly TNF-, LTα-, and LTβ-deficient mice share several phenotypic features, suggesting that TNF/LT signaling pathways may regulate overlapping sets of target genes. In order to directly address the issue of redundancy of TNF/LT signaling, we used the Cre-loxP recombination system to create mice with a deletion of the entire TNF/LT locus. Mice with a triple LTβ/TNF/LTα deficiency essentially manifest a combination of LT and TNF single-knockout phenotypes, except for microarchitecture of the spleen, where the disorder of lymphoid cell positioning and functional T- and B-cell compartmentalization is severer than that found in TNF or LT single-knockout mice. Thus, our data support the notion that TNF and LT have largely nonredundant functions in vivo.

scholarly journals LncRNA HANR Promotes Tumorigenesis and Increase of Chemoresistance in Hepatocellular Carcinoma

2017 ◽  
Vol 43 (5) ◽  
pp. 1926-1938 ◽  
Author(s):  
Jia Xiao ◽  
Yi Lv ◽  
Fujun Jin ◽  
Yingxia Liu ◽  
Yi Ma ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Therapeutic Target ◽  
Mice Model ◽  
Over Expression ◽  
In Vivo Experiments ◽  
Non Coding Rna ◽  
Promising Therapeutic Target ◽  
Induced Apoptosis ◽  
Pathway Analyses

Background/Aims: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third leading cause of cancer-related death. Critical roles for long non-coding RNAs (lncRNAs) have recently been demonstrated for a variety of cancers, including hepatocellular carcinoma. However, the effect and mechanism of lncRNAs in HCC tumorigenesis and chemoresistance have not been extensively characterized. Methods: In the current study, we have identified a HCC-expressed lncRNA termed as HANR (HCC associated long non-coding RNA). We identified HANR by microarray analysis and validated its up-regulated expression by quantitative PCR. RNA pull-down and pathway analyses were conducted to evaluate physical and functional interactions with HANR. In vivo experiments were performed to assess tumorigenesis and increase of chemoresistance. In addition, the HANR expression in HCC specimens was detected by FISH. Xenograft and orthotopic mice model was constructed to observe the effect of HANR on tumorigenesis and chemoresistance in vivo. Results: HANR was demonstrated to be up-regulated in HCC patients and HCC cell lines. Increased HANR expression in HCC predicted short survival of patients. Knock-down of HANR markedly retarded cell proliferation, suppressed HCC xenograft/orthotopic tumor growth, induced apoptosis and enhanced chemosensitivity to doxorubicin, while over-expression of HANR showed the opposite effects. It was found that HANR bind to GSKIP for regulating the phosphorylation of GSK3β in HCC. Conclusion: Our results demonstrate that HANR contributes to the development of HCC and is a promising therapeutic target for chemosensitization of HCC cells to doxorubicin, which may represent a promising therapeutic target in the future.

scholarly journals Vitamin D receptor pathway is required for probiotic protection in colitis

2015 ◽  
Vol 309 (5) ◽  
pp. G341-G349 ◽  
Author(s):  
Shaoping Wu ◽  
Sonia Yoon ◽  
Yong-Guo Zhang ◽  
Rong Lu ◽  
Yinglin Xia ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Knockout Mice ◽  
Target Genes ◽  
Lactobacillus Rhamnosus ◽  
Luciferase Reporter ◽  
Transcriptional Level ◽  
Probiotic Treatment

Low expression of vitamin D receptor (VDR) and dysfunction of vitamin D/VDR signaling are reported in patients with inflammatory bowel disease (IBD); therefore, restoration of VDR function to control inflammation in IBD is desirable. Probiotics have been used in the treatment of IBD. However, the role of probiotics in the modulation of VDR signaling to effectively reduce inflammation is unknown. We identified a novel role of probiotics in activating VDR activity, thus inhibiting inflammation, using cell models and VDR knockout mice. We found that the probiotics Lactobacillus rhamnosus strain GG (LGG) and Lactobacillus plantarum (LP) increased VDR protein expression in both mouse and human intestinal epithelial cells. Using the VDR luciferase reporter vector, we detected increased transcriptional activity of VDR after probiotic treatment. Probiotics increased the expression of the VDR target genes, such as antimicrobial peptide cathelicidin, at the transcriptional level. Furthermore, the role of probiotics in regulating VDR signaling was tested in vivo using a Salmonella-colitis model in VDR knockout mice. Probiotic treatment conferred physiological and histologic protection from Salmonella-induced colitis in VDR+/+mice, whereas probiotics had no effects in the VDR−/−mice. Probiotic treatment also enhanced numbers of Paneth cells, which secrete AMPs for host defense. These data indicate that the VDR pathway is required for probiotic protection in colitis. Understanding how probiotics enhance VDR signaling and inhibit inflammation will allow probiotics to be used effectively, resulting in innovative approaches to the prevention and treatment of chronic inflammation.

scholarly journals Runx2 and Runx3 differentially regulate articular chondrocytes during surgically induced osteoarthritis development

2021 ◽  
Author(s):  
Kosei Nagata ◽  
Hironori Hojo ◽  
Song Ho Chang ◽  
Hiroyuki Okada ◽  
Fumiko Yano ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Matrix Protein ◽  
Target Genes ◽  
Articular Chondrocytes ◽  
Type Ii Collagen ◽  
Conditional Knockout ◽  
Extracellular Matrix Protein ◽  
Surgically Induced

Abstract The Runt-related transcription factor (Runx) family plays various roles in the homeostasis of cartilage. Here, we examined the role of Runx2 and Runx3 for osteoarthritis (OA) development in vivo and in vitro. Runx3 knockout mice accelerated OA by surgical induction, accompanied with decreased expression of lubricin and aggrecan. Meanwhile, Runx2 conditional knockout mice showed biphasic phenotypes; OA was inhibited by hetero-knockout accompanied with decreased matrix metallopeptidase 13 (Mmp13) expression, but accelerated in homo-knockout of Runx2 accompanied with reduction of type II collagen (Col2a1) expression. Comprehensive transcriptional analyses revealed lubricin and aggrecan as transcriptional target genes of Runx3, and indicated that Runx2 sustained Col2a1 expression through an intron 6 enhancer when Sox9 was decreased. Intra-articular administration of Runx3 adenovirus ameliorated development of surgically induced OA. Runx3 protects adult articular cartilage through extracellular matrix protein production under the normal condition, while Runx2 exerts both catabolic and anabolic effects under the inflammatory condition.

Evaluation of chemokine-ligand pathways in pretreatment tumor biopsies as predictive biomarker of response to adoptive therapy in metastatic melanoma patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8576-8576 ◽  
Author(s):  
Davide Bedognetti ◽  
Sara Tomei ◽  
Tara L Spivey ◽  
Valeria De Giorgi ◽  
Maria Libera Ascierto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Copy Number Variation ◽  
Copy Number ◽  
Target Genes ◽  
Adoptive Therapy ◽  
Over Expression ◽  
Number Variation ◽  
Pre Treatment ◽  
Tumor Biopsies

8576 Background: Adoptive therapy with tumor infiltrating lymphocytes (TILs) induces objective responses (OR) in approximately 50% of patients with metastatic melanoma. The recruitment of TILs through CXCR3/CCR5-ligand chemokines is believed critical for immune-mediated rejection. Here, we investigated the predictive role of a gene-signature based on CXCR3/CCR5-ligand chemokine transcripts in pre-treatment melanoma biopsies, its biological role and its relation with CCR5-Δ32 polymorphism, which encodes a protein not expressed on cell surface. Methods: Expression of CXCR3/CXCR3-ligand transcripts (i.e CXCL9, 10, 11) and CCR5/CCR5-ligand transcripts (i.e. CCL3, 4, 5) were assessed in 113 pre-treatment tumor biopsies from patients enrolled in adoptive therapy trials: 24 patients achieved a complete remission (CR), 34 a partial remission (PR), and 55 did not respond (NR). Copy number variation and gene expression profile of these target genes were assessed in 15 biopsy-derived cell lines. CCR5-Δ32 was assessed by sequencing germinal DNA. Results: CXCL9, 10 and 11 and CCL5 clustered together and were selected for hierarchical clustering analysis based on the mean-centered gene expression values. A signature characterized by the over-expression of these genes was associated with the likelihood to achieve a clinical response (OR rate: PR+CR: 65% vs 38%, High vs Low, respectively, P=0.015). Neither correlation between the copy number variation and the gene-expression of the corresponding genes, nor correlation between the transcripts of the investigated genes between tumor biopsies and the matched cell lines was detected. Transcript expression of the target genes did not differ between CCR5-Δ32 (n =20) and wild type patients (n=93). Conclusions: Coordinate over-expression of CXCR3/CCR5 ligands in pre-treatment tumor samples was associated with responsiveness to treatment. However, the lack of correlation between in vivo and ex vivo data suggest the inflammatory status characterized by the up-regulation of these inflammatory chemokine genes is an in vivo multifactorial phenomenon.

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